No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
PGC-1 and exercise in the control of body weight
Abstract
The increasing prevalence of obesity and its comorbidities represents a major threat to human health globally. Pharmacological treatments exist to achieve weight loss, but the subsequent weight maintenance is prone to fail in the long run. Accordingly, efficient new strategies to persistently control body weight need to be elaborated. Exercise and dietary interventions constitute classical approaches to reduce and maintain body weight, yet people suffering from metabolic diseases are often unwilling or unable to move adequately. The administration of drugs that partially mimic exercise adaptation might circumvent this problem by easing and supporting physical activity. The thermogenic peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) largely mediates the adaptive response of skeletal muscle to endurance exercise and is a potential target for such interventions. Here, we review the role of PGC-1α in mediating exercise adaptation, coordinating metabolic circuits and enhancing thermogenic capacity in skeletal muscle. We suggest a combination of elevated muscle PGC-1α and exercise as a modified approach for the efficient long-term control of body weight and the treatment of the metabolic syndrome.International Journal of Obesity advance online publication, 31 January 2012; doi:10.1038/ijo.2012.12.
... The stepwise increase of food quantity in TG during the refeeding phase led to a rapid increase in BW by 34% of the previous BW loss. This may be attributed to specific metabolic mechanism such as the high metabolic plasticity of skeletal muscle (Summermatter and Handschin, 2012) that contributes to an elevated efficiency of energy utilization. This thrifty program and the lower energy expenditure after weight loss promotes the refilling of energy stores resulting in a rapid and efficient weight regain during refeeding (MacLean et al., 2006;Summermatter and Handschin 2012). ...
... This may be attributed to specific metabolic mechanism such as the high metabolic plasticity of skeletal muscle (Summermatter and Handschin, 2012) that contributes to an elevated efficiency of energy utilization. This thrifty program and the lower energy expenditure after weight loss promotes the refilling of energy stores resulting in a rapid and efficient weight regain during refeeding (MacLean et al., 2006;Summermatter and Handschin 2012). ...
... Analysis of body composition revealed that nearly all the energy, saved as a result of the adaptive changes in energy expenditure, is deposited as fat rather than protein (MacLean et al., 2006). However, part of the observed increase might be attributed to the recovery of skeletal muscle as indicated by Summermatter and Handschin (2012). Interestingly, the RHR increased in TG animals during the refeeding phase. ...
Domesticated horses are increasingly kept under semi-natural housing conditions, whereas their adaptation capacity is not fully investigated. In all, 10 Shetland pony mares were held under semi-extensive conditions for 1 year. In winter animals were allocated into two feeding groups (60% and 100% of maintenance energy requirement, respectively). Triiodothyronine, thyroxine, non-esterified fatty acids (NEFA), total bilirubin, total protein, triglyceride, glucose, insulin and hair length were measured at monthly intervals, whereas BW, body condition score, cresty neck score and resting heart rate were recorded every 2 weeks. From summer to winter all Ponies showed a reduction in resting heart rate ( P <0.001) and triiodothyronine ( P <0.001) but an increase in NEFA ( P <0.001), thyroxine ( P <0.001) and triglyceride ( P <0.001) concentrations. Feed restriction led to a reduced resting heart rate ( P =0.009), increased NEFA ( P <0.001) and total bilirubin ( P =0.008) concentrations. Thyroid hormones did not differ between feeding groups ( P >0.05). Refeeding of restrictively fed ponies resulted in a rapid increase in resting heart rate and BW and a return of blood parameters to reference values. Adequately supplied animals adapted without difficulty to varying environmental conditions, whereas feed restriction in ponies during winter resulted in reduced resting heart rates suggesting a reduced basal metabolic rate. The energy restriction was compensated by mobilizing body fat reserves which led to changes in blood parameters. Refeeding in feed restricted animals revealed a remarkably quick recovery of physiological and blood parameters to reference values. We therefore suggest that year round-outdoor housing can be a suitable housing system for robust horse breeds provided that an adequate food supply is available.
... Under the same conditions, the levels of p-JNK and p-ERK were significantly reduced by physical exercise in the SAT of obese subjects (P ϭ 0.013 and P ϭ 0.005, respectively; Fig. 6A). It has been shown previously that physical exercise has a positive effect on the expression of p-p38 MAPK and PGC-1␣ in the muscles of murine models and human subjects (3,66). Using the SAT and PBMCs from obese subjects before and after the physical exercise protocol, we observed a marginal increase in the levels of p-p38 MAP that did not reach statistical significance (Fig. 6, A and B); however, physical exercise did increase the expression of PGC-1␣ in the SAT at the mRNA level (P ϭ 0.0033; Fig. 7A) and protein level (P ϭ 0.03; Fig. 7B). ...
... In the white adipose tissue of obese, insulin-resistant, and diabetic subjects, the expression of PGC-1␣ expression is reduced (32,52,62). In contrast to the adipose tissue, PGC-1␣ is highly expressed in human skeletal muscle, and this expression is further enhanced by exercise in part through activation of the p38 MAPK signaling pathway (66). In agreement with The correlation was assessed by Spearman's rank correlation coefficient and based on the ⌬⌬CT method using lean (n ϭ 14) and obese (n ϭ 17) subjects from cohort study 1. these studies, we showed reduced expression of PGC-1␣ mRNA and protein in the SAT in obese subjects, which was concomitant with increased expression of DUSP1 and impairment of the p38 MAPK signaling pathway. ...
... In our study population, the exercise effect was also associated with decreased levels of TBARS and increased levels of ROS in the circulation, and this was consistent with other studies (1,70). Given the lack of a drastic effect of physical exercise on p-p38 MAPK, the increase in PGC-1␣ levels after physical exercise could be attributed to the increase of ROS, as reported previously (22,66). ...
... Under the same conditions, the levels of p-JNK and p-ERK were significantly reduced by physical exercise in the SAT of obese subjects (P ϭ 0.013 and P ϭ 0.005, respectively; Fig. 6A). It has been shown previously that physical exercise has a positive effect on the expression of p-p38 MAPK and PGC-1␣ in the muscles of murine models and human subjects (3,66). Using the SAT and PBMCs from obese subjects before and after the physical exercise protocol, we observed a marginal increase in the levels of p-p38 MAP that did not reach statistical significance (Fig. 6, A and B); however, physical exercise did increase the expression of PGC-1␣ in the SAT at the mRNA level (P ϭ 0.0033; Fig. 7A) and protein level (P ϭ 0.03; Fig. 7B). ...
... In the white adipose tissue of obese, insulin-resistant, and diabetic subjects, the expression of PGC-1␣ expression is reduced (32,52,62). In contrast to the adipose tissue, PGC-1␣ is highly expressed in human skeletal muscle, and this expression is further enhanced by exercise in part through activation of the p38 MAPK signaling pathway (66). In agreement with The correlation was assessed by Spearman's rank correlation coefficient and based on the ⌬⌬CT method using lean (n ϭ 14) and obese (n ϭ 17) subjects from cohort study 1. these studies, we showed reduced expression of PGC-1␣ mRNA and protein in the SAT in obese subjects, which was concomitant with increased expression of DUSP1 and impairment of the p38 MAPK signaling pathway. ...
... In our study population, the exercise effect was also associated with decreased levels of TBARS and increased levels of ROS in the circulation, and this was consistent with other studies (1,70). Given the lack of a drastic effect of physical exercise on p-p38 MAPK, the increase in PGC-1␣ levels after physical exercise could be attributed to the increase of ROS, as reported previously (22,66). ...
Chronic low-grade inflammation and uncontrolled metabolic stress response are cardinal features of obesity; a major risk factor for the development of diabetes. Dual specificity protein phosphatase 1 (DUSP1) is implicated in metabolism and energy expenditure. Mice lacking DUSP1 are resistant to high fat diet-induced obesity. However, the expression of DUSP1 has not been investigated in human obesity. In the current study, we compared the expression pattern of DUSP1 between lean and obese non-diabetic human subjects using subcutaneous adipose tissue and peripheral blood mononuclear cells. The levels of DUSP1 mRNA and protein were significantly increased in obese subjects with concomitant decrease in the phosphorylation of p38 MAPK and PGC-1α and an increase in the levels of phospho-JNK and phospho-ERK. Moreover, obese subjects had higher levels of circulating DUSP1 protein that correlated positively with various obesity indicators, triglycerides, glucagon, insulin, leptin and PAI-1 (P<0.05), but negatively with VO2, Max and high-density lipoprotein (P<0.05). The observation that DUSP1 was overexpressed in obese subjects prompted us to investigate if physical exercise could reduce its expression. In this study, we report for the first time that physical exercise significantly attenuated the expression of DUSP1 with a parallel increase in the expression of PGC-1α and a reduction in JNK and ERK activities along with attenuated inflammatory response. Collectively, our data suggest that DUSP1 upregulation is strongly linked to adiposity and physical exercise modulates its expression. This gives further evidence that exercise might be useful as a strategy for managing obesity and preventing its associated complications.
... Obesity and related metabolic disorders are increasingly recognized as major contributors to preventable death and increasing healthcare cost. It is forecasted that by 2030 over 85 % of adult Americans will be overweight, over 50 % of whom will be clinically obese which is associated with the development of several comorbidities including cancer, diabetes, hypertension, cardiovascular disease, and premature death [97,116]. Following a prudent diet by restricting energy intake and increasing energy expenditure through physical activity are two prominent behavioral modifications used to combat obesity and related disorders [25,97]. ...
... It is forecasted that by 2030 over 85 % of adult Americans will be overweight, over 50 % of whom will be clinically obese which is associated with the development of several comorbidities including cancer, diabetes, hypertension, cardiovascular disease, and premature death [97,116]. Following a prudent diet by restricting energy intake and increasing energy expenditure through physical activity are two prominent behavioral modifications used to combat obesity and related disorders [25,97]. Despite the consistent efficacy of diet and exercise to achieve weightloss, many fail to maintain such lifestyle changes and are unable to maintain ideal or healthy body weights [25,97]. ...
... Following a prudent diet by restricting energy intake and increasing energy expenditure through physical activity are two prominent behavioral modifications used to combat obesity and related disorders [25,97]. Despite the consistent efficacy of diet and exercise to achieve weightloss, many fail to maintain such lifestyle changes and are unable to maintain ideal or healthy body weights [25,97]. Due to the unsustainable nature for many people of behavioral modifications, patients and clinicians alike are interested in functional chemicals in dietary components, dietary supplements, and pharmaceuticals to aid in long-term weight loss. ...
Mitochondrial dysfunction has been linked to many diseases including metabolic diseases such as diabetes. Peroxisome proliferator-activated receptor gamma co-activator 1 (PGC-1) is a superfamily of transcriptional co-activators which are important precursors to mitochondrial biosynthesis found in most cells including skeletal muscle. The PGC-1 superfamily consists of three variants all of which are directly involved in controlling metabolic gene expression including those regulating fatty acid oxidation and mitochondrial proteins. In contrast to previous reviews on PGC-1, this mini-review summarizes the current knowledge of many known dietary stimulators of PGC-1 and the subsequent mitochondrial biosynthesis with associated metabolic benefit in skeletal muscle.
... However, the synthesis of ATP during training can be supported by antioxidants supplementation, which accelerate the process of muscle recovery after fatigue. There are evidences demonstrated a moderately beneficial effect of NAC ( Supinski et al., 1997;Sandstrom et al., 2006) and β-Alanine ( Stout et al., 2007;Ghiasvand et al., 2012;Summermatter and Handschin, 2012;Schnuck et al., 2016) supplementation for exercise with a substantial contribution from oxidative metabolism. It was shown unspecific antioxidant activity of NAC with increase GSH synthesis and reduce muscle-derived ROS levels during contraction (Sandstrom et al., 2006). ...
... It was shown unspecific antioxidant activity of NAC with increase GSH synthesis and reduce muscle-derived ROS levels during contraction (Sandstrom et al., 2006). Another study suggested a delay accumulation of lactate during exercise and increasing time to exhaustion under β-Alanine supplementation (Summermatter and Handschin, 2012). In our previous study, we showed a facilitation effect of water-soluble C 60 fullerenes on the removal of some symptoms of skeletal muscle fatigue ( Prylutskyy et al., 2017). ...
The aim of this study is to detect the effects of C60 fullerenes, which possess pronounced antioxidant properties, in comparison with the actions of the known exogenous antioxidants N-acetylcysteine (NAC) and β-Alanine in terms of exercise tolerance and contractile property changes of the m. triceps surae (TS) during development of the muscle fatigue in rats. The electrical stimulation of the TS muscle during four 30 min series in control rats led to total reduction of the muscle contraction force. Furthermore, the effects of prior intraperitoneal (i.p.) or oral C60FAS application and preliminary i.p. injection of NAC or β-Alanine on muscle contraction force under fatigue development conditions is studied. In contrast to control rats, animals with C60FAS, NAC, or β-Alanine administration could maintain a constant level of muscle effort over five stimulation series. The accumulation of secondary products and changes in antioxidant levels in the muscle tissues were also determined after the fatigue tests. The increased levels of lactic acid, thiobarbituric acid reactive substances and H2O2 after stimulation were statistically significant with respect to intact muscles. In the working muscle, there was a significant (p < 0.05) increase in the activity of endogenous antioxidants: reduced glutathione, catalase, glutathione peroxidase, and superoxide dismutase. Treated animal groups showed a decrease in endogenous antioxidant activity relative to the fatigue-induced animals (P < 0.05). Oral C60FAS administration clearly demonstrated an action on skeletal muscle fatigue development similar to the effects of i.p. injections of the exogenous antioxidants NAC or β-Alanine. This creates opportunities to oral use of C60FAS as a potential therapeutic agent. Due to the membranotropic activity of C60 fullerenes, non-toxic C60FAS has a more pronounced effect on the prooxidant-antioxidant homeostasis of muscle tissues in rats.
... Specifically, Smith et al. demonstrated a significant increase in VO2 peak, TTE, and total work completed in healthy male subjects supplemented with β-alanine for 6 weeks compared with un-supplemented controls, both of which received concurrent exercise training 26 . Remarkably, female subjects supplemented with 6.4g/day for the majority of the 28 day trial also exhibited increases in TTE, suggesting β-alanine may provide benefits similar to exercise training 27 . And while β-alanine is generally considered safe 2, 14, 16, 23, 24, some side effects such as skin irritation or burning sensation (otherwise known as paraesthesia) can occur 23 , leading some to caution the use of β-alanine until more is known about its safety 21 . ...
... And while β-alanine is generally considered safe 2, 14, 16, 23, 24, some side effects such as skin irritation or burning sensation (otherwise known as paraesthesia) can occur 23 , leading some to caution the use of β-alanine until more is known about its safety 21 . Multiple reviews exist regarding the efficacy and potential effects of β-alanine supplementation for improving athletic performance, however to the best of our knowledge, and despite the observations described above demonstrating β-alanine's ability to improve aerobic performance 11, 26, 27 , there have been no reports investigating the effect of β-alanine on indicators of oxidative metabolism in skeletal muscle 4, 21,24 . This report uniquely describes the effect of β-alanine on meta-Characterization of the metabolic effect of β-alanine on markers of oxidative metabolism and mitochondrial biogenesis in skeletal muscle [Purpose] β-alanine is a common component of numerous sports supplements purported to improve athletic performance through enhanced carnosine biosynthesis and related intracellular buffering. ...
Purpose:
β-alanine is a common component of numerous sports supplements purported to improve athletic performance through enhanced carnosine biosynthesis and related intracellular buffering. To date, the effects of β-alanine on oxidative metabolism remain largely unexplored. This work investigated the effects of β-alanine on the expression of proteins which regulate cellular energetics.
Methods:
C2C12 myocytes were cultured and differentiated under standard conditions followed by treatment with either β-alanine or isonitrogenous non-metabolizable control D-alanine at 800μM for 24 hours. Metabolic gene and protein expression were quantified by qRT-PCR and immunoblotting, respectively. Glucose uptake and oxygen consumption were measured via fluorescence using commercially available kits.
Results:
β-alanine-treated myotubes displayed significantly elevated markers of improved oxidative metabolism including elevated peroxisome proliferator-activated receptor β/δ (PPARβ/δ) and mitochondrial transcription factor a (TFAM) which led to increased mitochondrial content (evidenced by concurrent increases in cytochrome c content). Additionally, β-alanine-treated cells exhibited significantly increased oxygen consumption compared to control in a PPARβ/δ-dependent manner. β-alanine significantly enhanced expression of myocyte enhancer factor 2 (MEF-2) leading to increased glucose transporter 4 (GLUT4) content.
Conclusion:
β-alanine appears to increase cellular oxygen consumption as well as the expression of several cellular proteins associated with improved oxidative metabolism, suggesting β-alanine supplementation may provide additional metabolic benefit (although these observations require in vivo experimental verification).
... ROS play a dual role in IRI: they promote apoptosis and stimulate inflammatory mediators, as well as facilitate cell survival under hypoxic conditions and induce antioxidant defenses [42]. In a healthy liver, in response to IRI, levels of PGC-1α, which is a transcriptional coactivator that controls the expression of metabolic pathways, which allow for cellular adaptation to limited nutrient availability, are stimulated, and this stimulation results in increased antioxidant defenses of the cell [43,44]. Supporting this fact, Fukai et al. demonstrated increased total glutathione and reduced glutathione after IRI [45]. ...
Nutraceuticals are bioactive compounds present in foods, utilized to ameliorate health, prevent diseases, and support the proper functioning of the human body. They have gained attention due to their ability to hit multiple targets and act as antioxidants, anti-inflammatory agents, and modulators of immune response and cell death. Therefore, nutraceuticals are being studied to prevent and treat liver ischemia-reperfusion injury (IRI). This study evaluated the effect of a nutraceutical solution formed by resveratrol, quercetin, omega-3 fatty acid, selenium, ginger, avocado, leucine, and niacin on liver IRI. IRI was performed with 60 min of ischemia and 4 h of reperfusion in male Wistar rats. Afterward, the animals were euthanized to study hepatocellular injury, cytokines, oxidative stress, gene expression of apoptosis-related genes, TNF-α and caspase-3 proteins, and histology. Our results show that the nutraceutical solution was able to decrease apoptosis and histologic injury. The suggested mechanisms of action are a reduction in gene expression and the caspase-3 protein and a reduction in the TNF-α protein in liver tissue. The nutraceutical solution was unable to decrease transaminases and cytokines. These findings suggest that the nutraceuticals used favored the protection of hepatocytes, and their combination represents a promising therapeutic proposal against liver IRI.
... ROS play a dual role in IRI: they promote apoptosis and stimulate inflammatory mediators, as well as facilitating cell survival under hypoxic conditions and inducing antioxidant defenses [41]. In a healthy liver, in response to IRI, levels of PGC-1α, which is a transcriptional coactivator that controls the expression of metabolic pathways, which allow for cellular adaptation to limited nutrient availability, are stimulated, and this results in increased antioxidant defenses of the cell [42,43]. Supporting this fact, Fukai et al. demonstrated increased total glutathione and reduced glutathione after IRI [44]. ...
Nutraceuticals are bioactive compounds present in foods, utilized to ameliorate health, prevent diseases, and support the proper functioning of the human body. They have gained attention due to their ability to hit multi-targets and act as antioxidants, anti-inflammatory agents, and modulators of immune response and cell death. Therefore, nutraceuticals are being studied to prevent and treat liver ischemia–reperfusion injury (IRI). This study evaluated the effect of a nutraceutical solution formed by resveratrol, quercetin, omega-3 fatty acid, selenium, ginger, avocado, leucine, and niacin on liver IRI. IRI was performed with 60 min of ischemia and 4 hours of reperfusion in male Wistar rats. Afterward, the animals were euthanized to study hepatocellular injury, cyto-kines, oxidative stress, gene expression of apoptosis-related genes, TNF-alpha and Caspase 3 proteins, and histology. Our results show that the nutraceutical solution was able to decrease apoptosis and histologic injury. The suggested mechanisms of action are a reduction in gene expression and the Caspase 3 protein and a reduction in the TNF-alpha protein in liver tissue. The nutraceutical solution was unable to decrease transaminases and cytokines. These findings suggest that the nutraceuticals used favored the protection of hepatocytes and their combination represent a promising therapeutic proposal against liver IRI.
... Caloric restriction and exercise contribute to PGC1α activation and associated health outcomes [343][344][345][346][347][348]. Aligning meal times with the circadian rhythms by time-restricted feeding in animal models can also modulate PGC1α activity and mitochondrial biogenesis. ...
Obesity is a chronic and relapsing public health problem with an extensive list of associated comorbidities. The worldwide prevalence of obesity has nearly tripled over the last five decades and continues to pose a serious threat to wider society and the wellbeing of future generations. The pathogenesis of obesity is complex but diet plays a key role in the onset and progression of the disease. The human diet has changed drastically across the globe, with an estimate that approximately 72% of the calories consumed today come from foods that were not part of our ancestral diets and are not compatible with our metabolism. Additionally, multiple nutrient-independent factors, e.g., cost, accessibility, behaviours, culture, education, work commitments, knowledge and societal set-up, influence our food choices and eating patterns. Much research has been focused on ‘what to eat’ or ‘how much to eat’ to reduce the obesity burden, but increasingly evidence indicates that ‘when to eat’ is fundamental to human metabolism. Aligning feeding patterns to the 24-h circadian clock that regulates a wide range of physiological and behavioural processes has multiple health-promoting effects with anti-obesity being a major part. This article explores the current understanding of the interactions between the body clocks, bioactive dietary components and the less appreciated role of meal timings in energy homeostasis and obesity.
... Even if medical nutrition therapy containing 1200-1400 kcal is applied by individuals, it is not easy to achieve complete success adiposity; circadian nutrition; healthy eating; intermittent fasting; medical nutrition therapy; new dietary approaches; nutritional biochemistry (Erdal and Demirtas 2021;Ongan et al. 2021;Sahin, Sezerol, and Atak 2021). In addition, it is stated that in cases of body weight loss of more than 10% within 6 months or with low-energy diets, individuals gain more than they lost in 1-5 years (Meckling, O'Sullivan, and Saari 2004;Summermatter and Handschin 2012). For this reason, it is considered to be open to dispute whether the recommended medical nutrition therapy in obesity and its accompanying diseases is sustainable and effective enough in practice and getting results. ...
This review will examine the role of 5′-adenosine monophosphate-activated protein kinase (AMPK) in the treatment of obesity, medical nutrition and chronic diseases, and its relationship with nutrition. In the literature, the number of studies examining the direct relationship of AMPK with nutrition is negligible. For this reason, information on the subject has been compiled from all the studies that can be accessed by searching the terms AMPK and disease, AMPK and health, AMPK and exercise, AMPK and nutrition. It can be stated that AMPK is inhibited in many pathological conditions such as inflammation, diabetes, aging and cancer, and AMPK activation has positive effects in many diseases such as insulin resistance, diabetes, obesity, cancer and Alzheimer’s. When the relationship between nutrition and AMPK is examined, it is seen that food intake inhibits AMPK, but especially high-carbohydrate and fatty diets are more effective at this point. In addition, high fructose corn sirup and long chain saturated fatty acids increased by consumption of industrial foods and frequent meals appear to be an inactivator for AMPK. For AMPK activation in medical nutrition therapy, it is recommended to use methods such as evening fasting and intermittent fasting, taking into account the human circadian rhythm.
Keywords: Adiposity; circadian nutrition; healthy eating; intermittent fasting; medical nutrition therapy; new dietary approaches; nutritional biochemistry
... Physical activity can be referred to as any activity that is done at any time of day or night of any intensity [2]. Physical activity boosts energy expenditure and is a crucial factor in controlling body weight [3]. Despite the fact that the terms "physical activity" and "exercise" are sometimes used interchangeably, they have different connotations. ...
Background: Physical activity is a voluntary body movement which requires energy expenditure. Optimism makes an individual more resilient so if adversity strikes and the person has an upbeat attitude towards life, it is likely that an individual may bounce back stronger as before. The capacity to change or adjust to various situations may or may not depend on the level of physical activity and optimism in one’s life. The current study is aimed to determine the relationship between physical activity, optimism and resilience among general population of Aurangabad. Methods: This cross sectional study had a total of 531 respondents from across the city, out of which 228 were willing to participate. It included individuals from a age group of 18-52 years, of varying occupation. Outcome Measures: Three scales were used specifically. Life Orientation Test (LOT) was used to measure optimism. Brief Resilience Scale (BRS) was used to evaluate resilience and International Physical Activity Questionnaire (IPAQ) was used to measure the physical activity among the individuals. Results: The results were calculated using statistical tests. Chi-square test was used to find association between physical activity and optimism. The results showed a positive correlation between physical activity and optimism with a p value of > 0.05. The relation between optimism and resilience was calculated using Pearson’s correlation coefficient. Conclusion: The study signifies a strong positive correlation between optimism, resilience and physical activity among general population of Aurangabad. The study also concludes a positive correlation between optimism and resilience.
... Vücutta ağırlık kaybetmede büyük bir direnç oluşmaktadır ve birey zayıflamakta oldukça zorlanmaktadır. Bunun beraberinde yanlış beslenme alışkanlıkları, hatalı, hızlı ve sıkça tekrarlanan diyet uygulamaları, zayıflamak için bilgisizce kullanılan zayıflama ürünleri ve ilaçlar (diüretik, laksatif, vb.) Yo-Yo sendromunun gelişimine zemin hazırlamaktadır (Summermatter, 2012(Summermatter, : 1428. ...
Amaç: Obstrüktif uyku apne sendromu (OUAS), hastaların sağlıkla ilgili yaşam kalitesini ve duygusal durumunu etkileyen bir uyku bozukluğudur. Hastalık şiddetinin sağlıkla ilgili yaşam kalitesi, depresyon ve anksiyete için etkisi ise henüz net değildir. Çalışmanın amacı OUAS şiddetine göre hastaların yaşam kalitesi ile depresyon-anksiyete düzeyleri ve etkileşiminin incelenmesidir. Yöntem: Polisomnografi izlemi ile OUAS tanısı almış 60 hasta, hafif (n= 20), orta (n= 20) ve şiddetli (n= 20) uyku apne şikâyeti olan üç gruba ayrıldı. Hastalardan Kısa Form-36 ve Hastane Anksiyete Depresyon Ölçeğini doldurmaları istendi. Gruplar arası karşılaştırma ve korelasyon incelemesi için analizler gerçekleştirildi. Sonuç: Hastaların %66.7’si erkekti ve katılımcıların yaş ortalaması 45.4±9.7 yıldı. OUAS şiddetine göre hem anksiyete-depresyon hem de yaşam kalitesi skorlarında istatistiksel olarak gruplar arası anlamlı farklılık gözlenmedi (p>0.05). Sırasıyla hastaların depresyon ve anksiyete düzeyleri ile yaşam kalitesi alt başlıkları; fiziksel fonksiyon (r =-.364, r=-.652), fiziksel problemler nedeniyle olan kısıtlanma (r = -.468, r = -.693), emosyonel problemler nedeniyle olan kısıtlanma ( r = -.460, r = -.646), enerji / yorgunluk (r = -.579, r = -.649), emosyonel iyilik hali (r= -.437, r= -.543), sosyal fonksiyon (r = -.409, r = -.547), vücut ağrısı (r= -.582, r = -.815), genel sağlık algısı (r = -.688, r = -.738) arasında negatif yönlü ilişkiler olduğu belirlendi (p<0.05). Yorum: Araştırma sonuçları OUAS hastalarının biyopsikososyal iyilik hallerinin hastalık şiddetine göre farklılaşmadığını gösterdi. Bu hastalarda yaşam kalitesinin anksiyete ve depresyon ile yüksek düzeyde ilişkili olduğu, hastaların anksiyete ve depresyon düzeyleri arttıkça yaşam kalitelerinin düştüğü sonucu ortaya çıktı.
... Vücutta ağırlık kaybetmede büyük bir direnç oluşmaktadır ve birey zayıflamakta oldukça zorlanmaktadır. Bunun beraberinde yanlış beslenme alışkanlıkları, hatalı, hızlı ve sıkça tekrarlanan diyet uygulamaları, zayıflamak için bilgisizce kullanılan zayıflama ürünleri ve ilaçlar (diüretik, laksatif, vb.) Yo-Yo sendromunun gelişimine zemin hazırlamaktadır (Summermatter, 2012(Summermatter, : 1428. ...
Öz:
Obezite prevalansı son yıllarda artmış ve dünya çapında küresel sağlık sorunu haline gelmiştir. Vücut ağırlığı fazlalığı, yetişkinlerde ve çocuklarda yaygın olarak görülen bir sorundur ve tedavi edilmesi gerekmektedir. Dünya Sağlık Örgütü (DSÖ) obeziteyi, insan sağlığını tehdit edebilecek aşırı miktarda yağ depolanması olarak tanımlamaktadır. Bireylerin yanlış diyetler sonucunda sürekli olarak kilo alıp verme döngüsünde olması Dr. Kelly D. Brownell tarafından Yo-Yo Sendromu olarak tanımlanmıştır. Yo-Yo sendromunun oluşumunda metabolik ve fizyolojik faktörler etkili olmaktadır. Kısa sürede uygulanan, yanlış ve az kalorili diyetler Yo-Yo sendromunu ortaya çıkmasında etkili olmaktadır. Bu
sendroma sahip olan bireyler diyet yapmaya başladıklarında normal olarak ağırlık kaybederler fakat bu kaybedilen ağırlıklar uzun vadede kalıcı etkiye sahip değildir ve fazlasıyla geri kazanılmaktadır. Birey, kilo verip ardından hemen geri alarak kaçınılmaz ağırlık döngüsünün içine girmektedir. Yo-Yo sendromunun başarılı bir şekilde tedavi edilmesi ve bir daha yaşanmaması için beslenme ve diyet uzmanından destek alarak sağlıklı ağırlık kaybetmeyi hedefleyen kalıcı olan yaşam tarzı değişiklikleri benimsenerek
uzun vadede kilo kaybı sağlanmalıdır. Yo-Yo döngüsünün zarar verici etkilerinin ortadan kaldırılması, bireyin yaşam standartlarını yükselterek yerine ortalama yaşam süresinin artmasına ve mortalite oranının azalmasına neden olmaktadır. Bu çalışmada, Yo-Yo sendromu ve Yo-Yo sendromunun altında yatan metabolik ve fizyolojik etkenlerin literatür destekli olarak araştırılması amaçlanmaktadır. Sağlıklı bireylere sahip sağlıklı toplumların oluşmasında ve gelişmesinde sağlık profesyonellerinin rolü oldukça büyüktür. Multi-disipliner bir yaklaşım benimsenerek, bireylerin yaşam tarzı ve beslenme alışkanlıklarına
yönelik profesyonel müdahalelerin Yo-Yo döngüsüne karşın alınabilecek en etkili önlem olduğu düşünülmektedir.
Anahtar Kelimeler: Yo-Yo Sendromu, Beslenme, Obezite, Diyet, Ağırlık Kazanımı
... One of the major diseases related to obesity is NAFLD (non-alcoholic fatty liver disease), which consists of increased intrahepatic storage of triglycerides that reduces the metabolic activity in the liver and induces release of fat into the blood [4], increasing the risk of cardiovascular disease, acute myocardial infarction, hypertension, insulin resistance, glucose intolerance and type 2 diabetes [5][6][7]. Exercise alters the gene expression of CPT-1 (carnitine palmitoyl transferase 1), AMPK (AMP-activated protein kinase), ACC (acetyl-CoA carboxylase) and FAS (fatty acid synthase) in skeletal muscle and adipose tissue, which results in increased oxidative metabolic capacity and reduced lipogenesis; accordingly, exercise represents a relevant therapeutic tool to reduce body weight gain and the negative effects of obesity and type 2 diabetes [8][9][10]. In our previous study, we evaluated the role of swimming as exercise during pregnancy on the metabolic profile of F1 offspring fed a high-fat diet, and the results showed protection against HFD-induced obesity and a decrease in adipose depots in male offspring [11]. ...
Parental lifestyle has been related to alterations in the phenotype of their offspring. Obese sires can induce offspring insulin resistance as well as increase susceptibility to obesity. On the other hand, obese sires submitted to voluntary exercise ameliorate the deleterious metabolic effects on their offspring. However, there are no studies reporting the effect of programmed exercise training of lean sires on offspring metabolism.
Aims
This study aimed to investigate the role of swimming training of sires for 6 weeks on the offspring metabolic phenotype.
Main methods
Male C57BL/6 mice fed a control diet were divided into sedentary and swimming groups. After the exercise, they were mated with sedentary females, and body weight and molecular parameters of the offspring were subsequently monitored.
Key findings
Swimming decreased the gene expression of Fasn and Acaca in the testes and increased the AMPK protein content in the testes and epididymis of the sires. The progeny presented a low weight at P1, which reached a normal level at P60 and at P90 the animals were challenged with HFD for 16 weeks. The male offspring of trained sires presented less body weight gain than the control group. The level of steatosis decreased in the male offspring from trained sires. The gene expression of Prkaa2, Ppar-1α and Cpt-1 was also increased in the liver of male offspring from trained sires.
Significance
Taken together, these findings suggest that paternal exercise training can improve the metabolic profile in the liver of the progeny, thereby ameliorating the effects of obesity.
... 53,91,[96][97][98] Briefly, physical exertion increases a number of markers of cellular fitness, including but not limited to increases in AMPK, superoxide dismutases, brain-derived neurotrophic factor (BDNF), cyclic adenosine monophosphate response element-binding protein (CREB), peroxisome proliferatoractivated receptor g coactivator-1a (PGC1a), sirtuin 3 (SIRT3), calcium influx, and mitochondrial biogenesis. 51,62,99,100 For example, dietary restriction and exercise stimulate increased levels of PGC1a and circulating ketones (such as 3-b-hydroxybutyrate), which then induce the expression of BDNF to help maintain dendritic spines. 54,101,102 Exercise may also induce neuronal expression of SIRT3, which is known to mediate hormetic responses to oxidative, excitotoxic, and bioenergetic stressors through the hyperacetylation of mitochondrial superoxide dismutase 2 and cyclophilin D. 103 Benefits of a hormetic stimulus, such as dietary restriction, can be blocked by antioxidant supplementation, such as with the thiol N-acetyl cysteine, suggesting a mechanistic role for reactive oxygen species in the hormetic response. ...
Human performance, endurance, and resilience have biological limits that are genetically and epigenetically predetermined but perhaps not yet optimized. There are few systematic, rigorous studies on how to raise these limits and reach the true maxima. Achieving this goal might accelerate translation of the theoretical concepts of conditioning, hormesis, and stress adaptation into technological advancements. In 2017, an Air Force-sponsored conference was held at the University of Massachusetts for discipline experts to display data showing that the amplitude and duration of biological performance might be magnified and to discuss whether there might be harmful consequences of exceeding typical maxima. The charge of the workshop was “to examine and discuss and, if possible, recommend approaches to control and exploit endogenous defense mechanisms to enhance the structure and function of biological tissues.” The goal of this white paper is to fulfill and extend this workshop charge. First, a few of the established methods to exploit endogenous defense mechanisms are described, based on workshop presentations. Next, the white paper accomplishes the following goals to provide: (1) synthesis and critical analysis of concepts across some of the published work on endogenous defenses, (2) generation of new ideas on augmenting biological performance and resilience, and (3) specific recommendations for researchers to not only examine a wider range of stimulus doses but to also systematically modify the temporal dimension in stimulus inputs (timing, number, frequency, and duration of exposures) and in measurement outputs (interval until assay end point, and lifespan). Thus, a path forward is proposed for researchers hoping to optimize protocols that support human health and longevity, whether in civilians, soldiers, athletes, or the elderly patients. The long-term goal of these specific recommendations is to accelerate the discovery of practical methods to conquer what were once considered intractable constraints on performance maxima.
... The Summermatter Cycle describes how, initially during dieting, the energy expenditure of muscle reduces. Thus when more food becomes available, the more thrifty body favors the depositing of fat (Summermatter & Handschin, 2012). Such a mechanism illustrates that directing attention to the reduction of food intake, without realizing that it is the maintenance of weight loss that is important, is unlikely to be successful. ...
As the widespread availability of highly calorific food has resulted in a high incidence of obesity, attempts to decrease body weight have concentrated on trying to reduce energy intake. It is suggested that this is not the best approach. Although consuming more calories than expended is part of the initial problem, it does not follow that reducing intake, unless consciously counting calories, is the best solution. Mechanisms smooth out the large day-to-day differences in energy consumption, decreasing the importance of the size of a meal. In the short term a reduction in energy intake is counteracted by mechanisms that reduce metabolic rate and increase calorie intake, ensuring the regaining of lost weight. For example, even a year after dieting, hormonal mechanisms that stimulate appetite are raised. Over a million calories are consumed a year yet weight changes to only a small extent; there must be mechanisms that balance energy intake and expenditure. As obesity reflects only a small malfunctioning of these mechanisms, there is a need to understand the control of energy balance and how to prevent the regaining of weight after it has been lost. By itself, decreasing calorie intake will have a limited short-term influence.
... PGC-1α is a master regulator of mitochondrial biogenesis and activity [45]. Oxidative catabolism is associated with increased mitochondrial production of superoxide. ...
Reactive Oxygen Species (ROS) are key mediators of ischemia-reperfusion injury but also required for the induction of the stress response that limits tissue injury and underlies the protection provided by ischemic-preconditioning protocols. Liver steatosis is an important risk factor for liver transplant failure. Liver steatosis is associated with mitochondrial dysfunction and excessive mitochondrial ROS production. Studies aiming at decreasing the sensibility of the steatotic liver to ischemia-reperfusion injury using pre-conditioning protocols, have shown that the steatotic liver has a reduced capacity to respond to these protocols. Recent studies indicate that these effects are related to a reduced capacity of the steatotic liver to respond to elevated ROS levels following reperfusion by inducing a compensatory response. This failure to respond to ROS is associated with reduced levels of antioxidants, mitochondrial damage, hepatocyte cell death, activation of the immune system and induction of pro-fibrotic mediators.
... Peroxisome proliferator-activated receptor c coactivator-1a (PGC-1a) is a transcriptional coactivator that plays a central role in regulating mitochondrial function and oxidative capacity (7) by augmenting the expression of proteins that promote transcription of both nuclearencoded mitochondrial genes and mitochondrial DNA (8). Suppression of skeletal muscle PGC-1a is associated with increased energy intake (9,10) and the development of obesity, diabetes, and metabolic diseases (11). On the other hand, exercise is associated with increased expression of PGC-1a and has been shown to facilitate skeletal muscle mitochondrial adaptations, including enhanced mitochondrial biogenesis, bioenergetics, dynamics, and oxidative capacity (12,13). ...
Objective:
This study hypothesized that a low-glycemic diet combined with exercise would increase expression of nuclear regulators of fat transport and oxidation in insulin-resistant skeletal muscle.
Method:
Nineteen subjects (64 ± 1 y; 34 ± 1 kg/m(2) ) were randomized to receive isocaloric high-glycemic-index (HiGIX; 80 ± 0.6 units, n = 10) or low-glycemic-index (LoGIX; 40 ± 0.3 units, n = 9) diets combined with supervised exercise (1 h/d, 5 d/wk at ∼85% HRmax ) for 12 weeks. Insulin sensitivity was determined by hyperinsulinemic-euglycemic clamp. Skeletal muscle biopsies were obtained before and after the intervention to assess fasting gene and protein expression.
Results:
Weight loss was similar for both groups (9.5 ± 1.3 kg). Likewise, improvements in insulin sensitivity (P < 0.002) and PPARγ (P < 0.002), PGC-1α (P = 0.003), CD36 (P = 0.003), FABP3 (mRNA, P = 0.01 and protein, P = 0.02), and CPT1B (mRNA, P = 0.03 and protein, P = 0.008) expression were similar for both interventions. Increased insulin sensitivity correlated with increased PGC-1α expression (P = 0.04), and increased fasting fat oxidation correlated with increased FABP3 (P = 0.04) and CPT1B (P = 0.05) expression.
Conclusions:
An exercise/diet program resulting in 8% to 10% weight loss improved insulin sensitivity and key molecular mechanisms in skeletal muscle that are controlled by PGC-1α. These effects were independent of the glycemic index of the diets.
... The up-regulation of all respiratory complexes under copper treatment and downregulation with the addition of TBAP suggests that they are controlled by a master regulator. The peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) is the master regulator of mitochondrial biogenesis and is up-regulated by ATP demands and ROS (Irrcher et al., 2008;Lin et al., 2005;Mihaylova and Shaw, 2011;Summermatter and Handschin, 2012). Despite immunoblot experiments showed that PGC-1α expression increased over the control cells when exposed to copper and decreased when exposed to TBAP, those changes were not significantly different (p N 0.05, n = 9) (Fig. 6C). ...
Copper is integral to the mitochondrial respiratory complex IV and contributes to proliferation and differentiation, metabolic reprogramming and mitochondrial function. The K562 cell line was exposed to a non-cytotoxic copper overload to evaluate mitochondrial dynamics, function and cell fate. This induced higher rates of mitochondrial turnover given by an increase in mitochondrial fusion and fission events and in the autophagic flux. The appearance of smaller and condensed mitochondria was also observed. Bioenergetics activity included more respiratory complexes, higher oxygen consumption rate, superoxide production and ATP synthesis, with no decrease in membrane potential. Increased cell proliferation and inhibited differentiation also occurred. Non-cytotoxic copper levels can modify mitochondrial metabolism and cell fate, which could be used in cancer biology and regenerative medicine.
... Because capsaicin has previously been reported to modulate several cellular factors implicated in chronic metabolic disease such as diabetes and obesity, some believe capsaicin may hold some therapeutic benefit. For example, administration of capsaicin, capsiate, or capsaicinoids has been linked to elevated PGC-1a expression [18] which has been associated with reduced risk of metabolic disease and obesity [83,84]. These observations parallel numerous other studies demonstrating capsaicin may be beneficial for obesity, although few reports document consistent weight loss. ...
There is increasing interest in dietary chemicals that may provide benefits for pathologies such as diabetes and obesity. Capsaicinoids found in chili peppers and pepper extracts, are responsible for the "hot" or "spicy" sensation associated with these foods. Capsaicinoid consumption is also associated with enhanced metabolism, making them potentially therapeutic for metabolic disease by promoting weight loss. This review summarizes much of the current experimental evidence (ranging from basic to applied investigations) of the biochemical and molecular metabolic effects of capsaicinoids in metabolically significant cell types. Along with influencing metabolic rate, findings demonstrate capsaicinoids appear to alter molecular metabolic signaling, regulate hunger and satiety, blood metabolites, and catecholamine release. Notably, the majority of the experiments summarized herein utilized isolated supplemental or research grade capsaicinoids rather than natural food sources for experimental interventions. Additional work should be conducted using primary food sources of capsaicin to explore pharmacological, physiological, and metabolic benefits of both chronic and acute capsaicin consumption. © 2016 BioFactors, 2016.
... In athletes, accumulation of intramyocellular lipids might not be detrimental due to the constant substrate turnover in contraction-recuperation cycles: accordingly, musclespecific PGC-1␣ transgenic mice on a high fat diet exhibit markedly improved insulin sensitivity with concomitant physical activity to an even higher extent compared to wild-type control animals [102]. These findings imply that in addition to the transcriptional and translational changes that are elicited by an exercise "mimetic", other processes that are controlled by physical activity such as substrate turnover are required to achieve health benefits in certain contexts [103]. In fact, without changes in physical activity and diet, application of an exercise "mimetic" could thus be detrimental as observed in the high fat diet-fed, sedentary PGC-1␣ muscle-specific transgenic mice. ...
Exercise and diet are powerful interventions to prevent and ameliorate various pathologies. The development of pharmacological agents that confer exercise- or caloric restriction-like phenotypic effects is thus an appealing therapeutic strategy in diseases or even when used as life-style and longevity drugs. Such so-called exercise or caloric restriction "mimetics" have so far mostly been described in pre-clinical, experimental settings with limited translation into humans. Interestingly, many of these compounds activate related signaling pathways, most often postulated to act on the common downstream effector peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) in skeletal muscle. In this review, resveratrol and other exercise- and caloric restriction "mimetics" are discussed with a special focus on feasibility, chances and limitations of using such compounds in patients as well as in healthy individuals.
... At least experimentally, elevation of PGC-1α and its homolog PGC-1β indeed ameliorated several different muscle wasting pathologies in various mouse models of Duchenne muscular dystrophy [21,22] and a mitochondrial myopathy [23]. In the context of metabolic diseases, the results are less clear and it seems that bona fide physical activity is required to synergize the effect of overexpressed PGC-1α to improve diet-induced insulin resistance [24,25]. ...
An active lifestyle is crucial to maintain health into old age; inversely, sedentariness has been linked to an elevated risk for many chronic diseases. The discovery of myokines, hormones produced by skeletal muscle tissue, suggests the possibility that these might be molecular mediators of the whole body effects of exercise originating from contracting muscle fibers. Even though less is known about the sedentary state, the lack of contraction-induced myokines or the production of a distinct set of hormones in the inactive muscle could likewise contribute to pathological consequences in this context. In this review, we try to summarize the most recent developments in the study of muscle as an endocrine organ and speculate about the potential impact on our understanding of exercise and sedentary physiology, respectively.
... Obesity is an increasingly prevalent morbidity with nearly twothirds of adult Americans overweight, with over 32% of men and 35% of adult women clinically obese. 1 It is forecasted that roughly 85% of adult Americans will be overweight, over half of which will be clinically obese by 2030. 2,3 Over the past decade, chemical and behavioral interventions that favorably modify metabolic rate have been central to obesity research. Several over-the-counter dietary supplements claim to increase metabolic rate and enhance fatty acid catabolism. ...
Obesity is an increasingly prevalent and preventable morbidity with multiple behavioral, surgical and pharmacological interventions currently available. Commercial dietary supplements are often advertised to stimulate metabolism and cause rapid weight and/or fat loss, although few well-controlled studies have demonstrated such effects. We describe a commercially available dietary supplement (purportedly containing caffeine, catechins, and other metabolic stimulators) on resting metabolic rate in humans, and on metabolism, mitochondrial content, and related gene expression in vitro. Human males ingested either a placebo or commercially available supplement (RF) in a randomized double-blind placebo-controlled cross-over fashion. Metabolic rate, respiratory exchange ratio, and blood pressure were measured hourly for 3 h post-ingestion. To investigate molecular effects, human rhabdomyosarcoma cells (RD) and mouse myocytes (C2C12) were treated with various doses of RF for various durations. RF enhanced energy expenditure and systolic blood pressure in human males without altering substrate utilization. In myocytes, RF enhanced metabolism, metabolic gene expression, and mitochondrial content suggesting RF may target common energetic pathways which control mitochondrial biogenesis. RF appears to increase metabolism immediately following ingestion, although it is unclear if RF provides benefits beyond those provided by caffeine alone. Additional research is needed to examine safety and efficacy for human weight loss.
... In individuals with T2D, skeletal muscle PGC-1 mRNA levels are reduced 46 whereas the attenuated levels are restored by various types of exercise ranging from acute to chronic endurance. 47 Sutherland et al. 48 demonstrated that two hours of daily swimming exercise training for a month led to increases in markers of WAT mitochondrial biogenesis such as cytochrome-C oxidase (COXIV) and Core1 expression and citrate synthase activity, which are all driven by increased PGC-1 and mitochondrial transcription factor A (Tfam). ...
Our current environment has led to a vicious cycle of physical inactivity, obesity, and chronic inflammation, creating the "perfect storm" for metabolic diseases. White adipose tissue (WAT) is the major source of obesity/ inactivity-related inflammation; in turn, inflammation leads to insulin resistance and metabolic dysfunction. Inactivity, even in the absence of weight gain, disrupts WAT metabolism, while exercise mitigates WAT inflammation. The antiinflammatory mechanism(s) of exercise require additional study. Two current hypotheses include: (1) exercise-mediated antiinflammatory cytokine secretion, and (2) exercise-mediated improvements in adipocyte oxidative capacity.
... Accordingly, elevation of muscle PGC-1a in sedentary, high fat-fed mice accelerates the development of insulin resistance [81]. Importantly however, when combined with bona fide exercise, PGC-1a over-expression seems to be an efficient strategy to improve metabolic fitness under pathological conditions [82,83]. Importantly, HIT appears to be a more efficient approach to induce PGC-1a in skeletal muscle and improve whole body energy metabolism [59]. ...
Skeletal muscle energy metabolism is severely impaired in insulin resistant and type 2 diabetic patients. In particular, deregulated transcription of oxidative metabolism genes has been linked to the development of non-communicable metabolic diseases. The peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1α (PGC-1α) is a key molecule in the regulation of oxidative metabolism in different tissues, including skeletal muscle. In this tissue, physical exercise is one of the most dominant physiological stimuli to induce PGC-1α. In addition, exercise training efficiently prevents the development of metabolic diseases. Hence, better knowledge about the regulation of PGC-1α by exercise would significantly help to design effective treatments for these diseases.
... Overexpression of PGC-1␣ in muscle protects aging mice from age-related muscle wasting and glucose intolerance (50,52), and yet tight regulation of PGC-1␣ expression is required to maintain efficient glucose and lipid handling in obese mice (6,19,51). Expression of Pgc-1␣ in muscle is low in type 2 diabetics and related family members (2,21,33,38) but can be increased with exercise to possibly prevent or reverse metabolic abnormalities (3,25,44,49). Thus, a decline in Pgc-1␣ expression in aging muscle (8,13), brought on by factors such as diet, obesity, or decreased physical activity, may play a significant role in the age-associated development of glucose intolerance. ...
Diabetes risk increases significantly with age and correlates with lower oxidative capacity in muscle. Decreased expression of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (Pgc-1α) and target gene pathways involved in mitochondrial oxidative phosphorylation are associated with muscle insulin resistance, but a causative role has not been established. We sought to determine whether a decline in Pgc-1α and oxidative gene expression occurs during aging and potentiates the development of age-associated insulin resistance. Muscle-specific Pgc-1α knock-out (MKO) mice and wild-type littermate controls were aged for two years. Genetic signatures of skeletal muscle (microarray and mRNA expression) and metabolic profiles (glucose homeostasis, mitochondrial metabolism, body composition, lipids, and indirect calorimetry) of mice were compared at 3, 12, and 24 months of age. Microarray and gene set enrichment analysis highlighted decreased function of the electron transport chain as characteristic of both aging muscle and loss of Pgc-1α expression. Despite significant reductions in oxidative gene expression and succinate dehydrogenase activity, young mice lacking Pgc-1α in muscle had lower fasting glucose and insulin. Consistent with loss of oxidative capacity during aging, Pgc-1α and Pgc-1β expression were reduced in aged wild-type mouse muscle. Interestingly, the combination of age and loss of muscle Pgc-1α expression impaired glucose tolerance and led to increased fat mass, insulin resistance, and inflammatory markers in white adipose and liver tissues. Therefore, loss of Pgc-1α expression and decreased mitochondrial oxidative capacity contributes to worsening glucose tolerance and chronic systemic inflammation associated with aging.
... People suffering from metabolic disorders often are unable or unwilling to achieve the levels of physical activity that are required to elicit health benefits. The auxiliary use of substances that mimic the plastic adaptations to exercise, so-called exercise mimetics (8), constitutes a seemingly attractive therapeutic approach to ease and support physical activity or amplify the effects of exercise, at least when potential drawbacks and limitations are ignored (9,10). As a key regulator of muscle plasticity (11,12), the peroxisome proliferator–activated receptor γ coactivator 1α (PGC-1α) constitutes a potential target for such drugs (13). ...
Metabolic disorders are a major burden for public health systems globally. Regular exercise improves metabolic health. Pharmacological targeting of exercise mediators might facilitate physical activity or amplify the effects of exercise. The peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) largely mediates musculoskeletal adaptations to exercise, including lipid refueling, and thus constitutes such a putative target. Paradoxically, forced expression of PGC-1α in muscle promotes diet-induced insulin resistance in sedentary animals. We show that elevated PGC-1α in combination with exercise preferentially improves glucose homeostasis, increases Krebs cycle activity, and reduces the levels of acylcarnitines and sphingosine. Moreover, patterns of lipid partitioning are altered in favor of enhanced insulin sensitivity in response to combined PGC-1α and exercise. Our findings reveal how physical activity improves glucose homeostasis. Furthermore, our data suggest that the combination of elevated muscle PGC-1α and exercise constitutes a promising approach for the treatment of metabolic disorders.
Peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) family (PGC-1s), consisting of three members encompassing PGC-1α, PGC-1β, and PGC-1-related coactivator (PRC), was discovered more than a quarter-century ago. PGC-1s are essential coordinators of many vital cellular events, including mitochondrial functions, oxidative stress, endoplasmic reticulum homeostasis, and inflammation. Accumulating evidence has shown that PGC-1s are implicated in many diseases, such as cancers, cardiac diseases and cardiovascular diseases, neurological disorders, kidney diseases, motor system diseases, and metabolic disorders. Examining the upstream modulators and co-activated partners of PGC-1s and identifying critical biological events modulated by downstream effectors of PGC-1s contribute to the presentation of the elaborate network of PGC-1s. Furthermore, discussing the correlation between PGC-1s and diseases as well as summarizing the therapy targeting PGC-1s helps make individualized and precise intervention methods. In this review, we summarize basic knowledge regarding the PGC-1s family as well as the molecular regulatory network, discuss the physio-pathological roles of PGC-1s in human diseases, review the application of PGC-1s, including the diagnostic and prognostic value of PGC-1s and several therapies in pre-clinical studies, and suggest several directions for future investigations. This review presents the immense potential of targeting PGC-1s in the treatment of diseases and hopefully facilitates the promotion of PGC-1s as new therapeutic targets.
Adipose tissue is an essential body organ that is profoundly affected by both exercise and female sex hormones. As the body’s major energy reservoir, adipose tissue is extremely sensitive to exercise. That is, exercise-mediated increases in circulating catecholamines are a major stimulus for adipocyte lipolysis, the process that allows for mobilization of the lipid stored in adipose tissue for use by other cells of the body. A major physiological and anatomical difference between sexes is that females have significantly more relative adipose tissue. This important difference is clearly mediated by female sex hormones (e.g., estrogen), which dictate body fat distribution patterns, and appear to also affect the physiological function of adipose tissue. For example, ovary-intact female adipose tissue appears to be more metabolically active and less susceptible to insulin resistance and inflammation compared to that from age-matched males. There are also important differences between males and females in brown adipose tissue (BAT) metabolism, such that females have more relative BAT than males and BAT from females appears more active. Moreover, the signature protein expressed in BAT, uncoupling protein-1 (UCP-1), is also more highly expressed in white adipose tissue (WAT) of females, and exercise has been shown to induce WAT UCP-1, a process associated with improved metabolic health. It is likely that estrogen plays a large role in those sex differences and estrogen receptors likely mediate those effects. Finally, there are many interesting similarities between how exercise and estrogen affect the function of adipose tissue. The purpose of this chapter is to provide the reader with a basic understanding of the how exercise and estrogen affect adipose tissue physiology and function; this is done via a comprehensive overview of the most recent scientific literature on this topic.KeywordsAdipose tissueEstrogen receptorMetabolismBATBrown adiposeWATMitochondrial functionExerciseInflammationSex
Type 2 diabetes (T2D) is associated with chronic inflammation as a critical factor for muscle atrophy and disease progression. Although the combination of aerobic and resistance training leads to more significant improvements in health-related indices for T2D patients, the interference effect in concurrent training can decrease positive adaptations. The purpose of this study was to investigate the physiological adaptations in performing high-intensity interval training (HIIT) and resistance training on the same day vs. different days in T2D patients. Twenty-four non-athletic 45–65-year-old women with T2D participated in an 8-week intervention. They were randomly divided into three groups: same days (SD), different days (DD), and treatment as usual (control). SD group had resistance training followed by HIIT on Saturday, Monday, and Wednesday. In contrast, the DD group had the same volume of resistance training on Saturday, Monday, and Wednesday and HIIT on Sunday, Tuesday, and Thursday, with Friday as a resting day. Blood samples were collected 24 h before the first and 48 h after the last session in each group to measure glucose, insulin, glycosylated hemoglobin, IGF1, IL1β, CRP, lipid profile, miR-146a, and miR-29b. Three subjects dropped out during the study, and 21 participants (SD = 7, DD = 6, Control = 8) completed the 8-week intervention. MiR-146a changed significantly (P = 0.006) in both SD and DD groups compared to the control group. IGF1 (P = 0.001) and fat-free mass (P = 0.001) changed significantly in SD and DD groups compared to the control group, and also DD led to more significant increases in IGF1 and fat-free mass in comparison with SD. MiR-29 (P = 0.001) changed significantly in the DD group compared to the control group. The reduction of IL-1β, fat mass and insulin resistance was significant in SD and DD compared to the control group; DD showed more potent effects than the SD group on the fat mass (P = 0.001) and insulin resistance (P = 0.001). This study demonstrated that a combination of HIIT and resistance training could be practical for improving health-related outcomes in T2D. Our study indicated for the first time that training strength and HIIT on separate days appeared to be more effective to combat muscle atrophy and insulin resistance.
The overall aim of this chapter is to investigate the possibility that environmental factors are driving the obesity pandemic by causing epigenetic changes during development and throughout life. A background on the role of epigenetics in variable obesity predisposition is provided, covering obesity-associated diseases (Prader Willi syndrome and Angelman syndrome) and imprinted genes such as IGF2/H19. Several human-based studies assessing potential contributing environmental factors are then discussed, including investigations into possible mechanisms by which they alter epigenetic profiles to promote obesity and obesity associated diseases such as T2D. The effects of parental exposure, aging, and lifestyle on obesity epigenetics is also extensively evaluated. The chapter finishes with an overview on the potential for using epigenetic treatments to combat obesity, particularly looking at how physical activity can reverse obesity-associated epigenetic marks.
Background:
Mobile apps for weight loss provide users with convenient features for recording lifestyle and health indicators; they have been widely used for weight loss recently. Previous studies in this field generally focused on the relationship between the cumulative nature of self-reported data and the results in weight loss at the end of the diet period. Therefore, we conducted an in-depth study to explore the relationships between adherence to self-reporting and weight loss outcomes during the weight reduction process.
Objective:
We explored the relationship between adherence to self-reporting and weight loss outcomes during the time series weight reduction process with the following 3 research questions: "How does adherence to self-reporting of body weight and meal history change over time?", "How do weight loss outcomes depend on weight changes over time?", and "How does adherence to the weight loss intervention change over time by gender?"
Methods:
We analyzed self-reported data collected weekly for 16 weeks (January 2017 to March 2018) from 684 Korean men and women who participated in a mobile weight loss intervention program provided by a mobile diet app called Noom. Analysis of variance (ANOVA) and chi-squared tests were employed to determine whether the baseline characteristics among the groups of weight loss results were different. Based on the ANOVA results and slope analysis of the trend indicating participant behavior along the time axis, we explored the relationship between adherence to self-reporting and weight loss results.
Results:
Adherence to self-reporting levels decreased over time, as previous studies have found. BMI change patterns (ie, absolute BMI values and change in BMI values within a week) changed over time and were characterized in 3 time series periods. The relationships between the weight loss outcome and both meal history and self-reporting patterns were gender-dependent. There was no statistical association between adherence to self-reporting and weight loss outcomes in the male participants.
Conclusions:
Although mobile technology has increased the convenience of self-reporting when dieting, it should be noted that technology itself is not the essence of weight loss. The in-depth understanding of the relationship between adherence to self-reporting and weight loss outcome found in this study may contribute to the development of better weight loss interventions in mobile environments.
Siegesbeckia orientalis has been reported to exhibit anti-allergic, anti-infertility, anti-inflammatory, anti-rheumatic, and immunosuppressive activities. However, there are very few studies describing its stimulatory effects on exercise capacity. This study elucidated whether S. orientalis extract (SOE) standardized to kirenol content can enhance exercise endurance by increasing mitochondrial biogenesis. SOE significantly improved the running distance and time in mice fed normal diet (ND) and high-fat diet (HFD). SOE also enhanced mitochondrial biogenesis by stimulating the mitochondrial regulatory genes including peroxisome proliferator-activated receptor gamma co-activator 1 alpha (PGC-1α), estrogen-related receptor α (ERRα), nuclear respiratory factor 1 (NRF-1), and mitochondrial transcription factor A (TFAM) in the skeletal muscles of ND and HFD mice. Furthermore, SOE upregulated the AMP-activated protein kinase (AMPK)/sirtuin 1 (SIRT1)/PGC-1α/peroxisome proliferator-activated receptor delta (PPARδ) signaling pathway in the skeletal muscles of ND and HFD mice. Kirenol markedly increased adenosine triphosphate production and mitochondrial activity by stimulating the expression of markers of mitochondrial biogenesis and upregulating the AMPK/SIRT1/PGC-1α/PPARδ signaling pathway in L6 myotubes. These results show that SOE has the potential to be used to develop an exercise supplement capable of stimulating mitochondrial biogenesis through the AMPK/SIRT1/PGC-1α/PPARδ signaling pathway.
Branched-chain amino acids (BCAAs) are essential in the diet and may provide benefit for those who partake in regular physical activity and resistance training, yet circulating BCAAs have been repeatedly shown to correlate with severity of insulin resistance in obese/diseased populations. Recently, the valine catabolite 3-hydroxyisobuterate (3HIB) was shown to promote insulin resistance in skeletal muscle by increasing lipid content in vivo. The purpose of this study was to investigate the mechanistic effects of 3HIB on skeletal muscle insulin signaling, metabolism, and related gene expression in vitro. Given these previous observations, we hypothesized that 3HIB would depress skeletal muscle metabolism and insulin sensitivity. C2C12 myotubes were treated with 3HIB for up to 48 hours using both physiological (25-100 μmol/L) and supraphysiological (5 mmol/L) concentrations. Metabolic gene expression was measured via quantitative real-time polymerase chain reaction, mitochondrial metabolism was measured via O 2 consumption, and glycolytic metabolism was quantified using extracellular acidification rate. Western blot was used to assess insulin sensitivity following insulin stimulation (indicated by phospho-AKT expression). 3HIB did not alter expressional indicators of mitochondrial biogenesis, glycolysis, BCAA catabolism, or lipogenesis. Chronic physiological 3HIB treatment significantly increased peak oxygen consumption, whereas supraphysiological 3HIB treatment suppressed basal and peak mitochondrial and glycolytic metabolism. Both physiological and supraphysiological 3HIB reduced pAkt expression during insulin stimulation. These findings suggest that 3HIB may reduce muscle insulin sensitivity in cultured myotubes, supporting a potentially causal role of 3HIB in the development of insulin resistance in highly metabolic cell types.
Branched‐chain amino acids (BCAA) such as leucine stimulate favorable metabolic processes involved in lean tissue preservation and skeletal muscle metabolism. However, higher levels of circulating BCAA correlate with severity of metabolic disease (including diabetes/insulin resistance), and may result from dysregulated BCAA catabolism. Past observations have demonstrated potential interaction between BCAA and dietary fat; however, much of this relationship remains underexplored. This study investigated the effect of leucine both with and without palmitate on oxidative and glycolytic metabolism, as well as indicators of BCAA catabolism using cultured skeletal muscle cells. Specifically, C2C12 myotubes were treated with or without varying concentrations of leucine both with and without palmitate for 24 h. Leucine treatment significantly elevated mRNA expression of metabolic regulators including peroxisome proliferator‐activated receptor‐gamma coactivator 1‐alpha versus leucine with concurrent palmitate treatment. Interestingly, leucine‐only, palmitate‐only, and leucine with palmitate all significantly increased cellular lipid content, which translated into significantly increased oxidative capacity under substrate‐limited conditions. However, upon the addition of excess substrate and carnitine, discrepancies in peak metabolic capacities between various treatments were no longer observed, suggesting leucine, palmitate, or the combination thereof causes a shift in metabolic preference from glycolytic to oxidative. These data also suggest leucine's effect on mitochondrial metabolism may result in part from increased lipid stores in addition to other previously documented pathways.
Branched-chain amino acids (BCAAs) appear to influence several synthetic and catabolic cellular signaling cascades leading to altered phenotypes in mammals. BCAAs are most notably known to increase protein synthesis through modulating protein translation, explaining their appeal to resistance and endurance athletes for muscle hypertrophy, expedited recovery, and preservation of lean body mass. In addition to anabolic effects, BCAAs may increase mitochondrial content in skeletal muscle and adipocytes, possibly enhancing oxidative capacity. However, elevated circulating BCAA levels have been correlated with severity of insulin resistance. It is hypothesized that elevated circulating BCAAs observed in insulin resistance may result from dysregulated BCAA degradation. This review summarizes original reports that investigated the ability of BCAAs to alter glucose uptake in consequential cell types and experimental models. The review also discusses the interplay of BCAAs with other metabolic factors, and the role of excess lipid (and possibly energy excess) in the dysregulation of BCAA catabolism. Lastly, this article provides a working hypothesis of the mechanism(s) by which lipids may contribute to altered BCAA catabolism which often accompanies metabolic disease.
Adipose tissue is an essential body organ that is profoundly affected by both exercise and female sex hormones. As the body’s major energy reservoir, adipose tissue is extremely sensitive to exercise. That is, exercise-mediated increases in circulating catecholamines are a major stimulus for adipocyte lipolysis, the process that allows for mobilization of the lipid stored in adipose tissue for use by other cells of the body. A major physiological and anatomical difference between sexes is that females have significantly more relative adipose tissue. This important difference is clearly mediated by female sex hormones (e.g., estrogen), which dictate body fat distribution patterns, and appear to also affect the physiological function of adipose tissue. For example, ovary-intact female adipose tissue appears to be more metabolically active and less susceptible to insulin resistance and inflammation compared to that from age-matched males. There are also important differences between males and females in brown adipose tissue (BAT) metabolism, such that females have more relative BAT than males and BAT from females appears more active. It is likely that the female hormone, estrogen plays a large role in those sex differences and estrogen receptor alpha appears to mediate those effects. Finally, there are many interesting similarities between how exercise and estrogen affect the function of adipose tissue. The purpose of this chapter is to provide the reader with a basic understanding of the how exercise and estrogen affect adipose tissue physiology and function; this is done via a comprehensive overview of the most recent scientific literature on this topic.
Objective:
Reduction of body fat can be achieved by dietary programs and/or aerobic exercise training. More convenient methods to rid the body of excess fat are needed. However, it is unclear whether it is possible to more easily lose body weight at all.
Methods:
DUhTP mice bred through phenotype selection for high treadmill performance and unselected controls were voluntarily physically active in a running wheel over a period of 3 weeks. Phenotypical data were collected, and subcutaneous fat was analyzed for expression of mitochondria-relevant proteins.
Results:
Voluntary physical activity over 3 weeks exclusively in DUhTP mice severely reduced subcutaneous (-38%; p < 0.05) and epididymal (-32%; p < 0.05) fat. Following mild physical activity, subcutaneous fat derived from DUhTP mice showed increased levels of long chain acyl dehydrogenase (LCAD; +230%; p < 0.05) and peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1-α; p < 0.01). Mitochondrial transcription factor A (Tfam) expression was similar in both sedentary genotypes but physical activity increased Tfam levels exclusively in DUhTP (p < 0.05).
Conclusion:
Our findings indicate that the mitochondrial mass is highly active in DUhTP mice and responsive even to mild physical activity. While genetic predisposition could not prevent fat accretion in DUhTP mice, voluntary activity was sufficient to reduce excess body fat almost completely.
Jedes Jahr, insbesondere im Frühling und zum Auftakt der Badesaison, tauchen vor allem auch in den Online-Medien neue Diättrends auf und verheißen eine Gewichtsreduktion auf einfachem Weg. Doch welche Kostformen können empfohlen werden? Für welche Strategie gibt es Evidenz? Und was, wenn die Kilos wirklich weggeschmolzen sind? Lassen Sie sich auf den aktuellen Stand bringen!
The world-wide epidemic of obesity is now affecting up to a third of the adult population. Research attempting to contribute to management of this health scourge has been recently refocused on the essential role of physical activity. Muscle activity induces a dramatic increase in transcription of the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). This protein is a regulator of mitochondrial biogenesis and function. Very recently, in 2014 it was revealed that the mediator of this metabolic process is a low molecular myokine, the beta- aminoisobutyric acid (BAIBA). This compound with a simple molecular structure has a key metabolic role: it converts the cells of white adipose tissue into brown fat. The brown adipocytes contain a protein thermogenin. This substance turns off the energy stores, among others the adenosine triphosphate (ATP), thereby accelerating the breakdown of lipids into heat, water and CO2. We may be at the threshold of new and effective management of obesity. The world eagerly expects to see how the BAIBA will compare with other recently reported agents to fight the overweight (Fig. 2, Ref. 6).
Exercise offers several benefits for health, many of which promote an increased metabolic rate and energy expenditure. A myokine known as irisin was recently identified to promote increased metabolic rate, adipocyte browning, and mitochondrial biogenesis, however the effects have yet to be explored in skeletal muscle.
This work explored the effects of irisin on metabolism, gene expression, and mitochondrial content in cultured myocytes.
C2C12 myocytes were treated with various concentrations of irisin for various durations. Glycolysis and oxidative metabolism were quantified by measurement of extracellular acidification and oxygen consumption, respectively. Metabolic gene expression was measured by qRT-PCR and mitochondrial content was assessed by flow cytometry and confocal microscopy.
Cells treated with irisin exhibited significantly increased oxidative metabolism. Irisin treatment also significantly increased mitochondrial uncoupling at various doses and durations. Lastly, treatment with irisin also significantly elevated metabolic gene expression including peroxisome proliferator-activated receptor γ coactivator 1 alpha (PGC-1α), nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (TFAM), irisin, glucose transporter 4 (GLUT4), and mitochondrial uncoupling protein 3 (UCP3) leading to increased mitochondrial biogenesis.
Our observations are the first to document increased metabolism in myocytes through irisin-mediated induction of mitochondrial biogenesis and uncoupling with corresponding gene expression. These observations support the need for further investigation into the therapeutic and pharmacological effects of irisin, as well as development of irisin-based therapy.
Glycogen is an energy storage depot for the mammalian species. This review focuses on recent developments that have identified the role of nuclear hormone receptor (NR) signaling and epigenomic control in the regulation of important genes that modulate glycogen metabolism. Specifically, new studies have revealed that the NR4A subgroup (of the NR superfamily) are strikingly sensitive to beta-adrenergic stimulation in skeletal muscle, and transgenic studies in mice have revealed the expression of these NRs affects endurance and glycogen levels in muscle. Furthermore, other studies have demonstrated that one of the NR coregulator class of enzymes that mediate chromatin remodeling, the histone methyltransferases (for example, protein arginine methyltransferase 4) regulates the expression of several genes involved in glycogen metabolism and glycogen storage diseases in skeletal muscle. Importantly, NRs and histone methyltransferases, have the potential to be pharmacologically exploited and may provide novel targets in the quest to treat disorders of glycogen storage. © 2013 IUBMB Life, 2013.
The peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) controls metabolic adaptations. We now show that PGC-1α in skeletal muscle drives the expression of lactate dehydrogenase (LDH) B in an estrogen-related receptor-α-dependent manner. Concomitantly, PGC-1α reduces the expression of LDH A and one of its regulators, the transcription factor myelocytomatosis oncogene. PGC-1α thereby coordinately alters the composition of the LDH complex and prevents the increase in blood lactate during exercise. Our results show how PGC-1α actively coordinates lactate homeostasis and provide a unique molecular explanation for PGC-1α-mediated muscle adaptations to training that ultimately enhance exercise performance and improve metabolic health.
AMP-activated protein kinase (AMPK) β1 or β2 subunits are required for assembling of AMPK heterotrimers and are important
for regulating enzyme activity and cellular localization. In skeletal muscle, α2β2γ3-containing heterotrimers predominate.
However, compensatory up-regulation and redundancy of AMPK subunits in whole-body AMPK α2, β2, and γ3 null mice has made it
difficult to determine the physiological importance of AMPK in regulating muscle metabolism, because these models have normal
mitochondrial content, contraction-stimulated glucose uptake, and insulin sensitivity. In the current study, we generated
mice lacking both AMPK β1 and β2 isoforms in skeletal muscle (β1β2M-KO). β1β2M-KO mice are physically inactive and have a
drastically impaired capacity for treadmill running that is associated with reductions in skeletal muscle mitochondrial content
but not a fiber-type switch. Interestingly, young β1β2M-KO mice fed a control chow diet are not obese or insulin resistant
but do have impaired contraction-stimulated glucose uptake. These data demonstrate an obligatory role for skeletal muscle
AMPK in maintaining mitochondrial capacity and contraction-stimulated glucose uptake, findings that were not apparent in mice
with single mutations or deletions in muscle α, β, or γ subunits.
Activation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α)-mediated transcription is important for both the determination of mitochondrial content and the induction of mitochondrial biogenesis in skeletal muscle. SIRT1 (silent mating type information regulator 2 homolog 1) deactetylation is proposed as a potential activator of PGC-1α transcriptional activity. The current review examines the importance of SIRT1 deacetylation of PGC-1α in skeletal muscle. Models of SIRT1 overexpression and pharmacological activation are examined, but changes in SIRT1 expression and deacetylase activity following acute and chronic contractile activity will be emphasized. In addition, potential mechanisms of SIRT1 activation in skeletal muscle will be examined. The importance of the PGC-1α acetyltransferase GCN5 will also be briefly discussed. The current evidence supports the contribution of SIRT1 deacetylation of PGC-1α to exercise-induced mitochondrial biogenesis. Further research examining exercise-mediated activation of SIRT1 and the role of GCN5 in regulating PGC-1α transcriptional activity in skeletal muscle is required.
The present study investigated whether exercise induces the expression of PGC-1α splice variants in human skeletal muscle and the possible influence of metabolic perturbation on this response. The subjects exercised one leg for 45 min with restricted blood flow (R-leg), followed by 45 min of exercise using the other leg at the same absolute workload but with normal blood flow (NR-leg). This ischemic model (R-leg) has been shown previously to induce a greater metabolic perturbation and enhance the expression of PGC-1α beyond that observed in the NR-leg. Cultured human myotubes were used to test suggested exercise-induced regulatory stimuli of PGC-1α. We showed, for the first time, that transcripts from both the canonical promoter (PGC-1α-a) and the proposed upstream-located promoter (PGC-1α-b) are present in human skeletal muscle. Both transcripts were upregulated after exercise in the R-leg, but the fold change increase of PGC-1α-b was much greater than that of PGC-1α-a. No differences were observed between the two conditions regarding the marker for calcineurin activation, MCIP1, or p38 phosphorylation. AMPK phosphorylation increased to a greater extent in the R-leg, and AICAR stimulation of cultured human myotubes induced the expression of PGC-1α-a and PGC-1α-b. AICAR combined with norepinephrine yielded an additive effect on the PGC-1α-b expression only. Our results indicate clearly that exercise can activate an upstream promoter in humans and support AMPK as a major regulator of transcripts from the canonical PGC-1α promoter and the involvement of β-adrenergic stimulation in combination with AMPK in the regulation of PGC-1α-b.
Although it is no longer debatable that sedentary behaviors are an actual cause of many metabolic diseases, the physiology of physical inactivity has been poorly investigated for this purpose. Along with microgravity, the physiological adaptations to spaceflights require metabolic adaptations to physical inactivity, and that is exceedingly well-simulated during the ground-based microgravity bed-rest analogs. Bed rest thus represents a unique model to investigate the mechanisms by which physical inactivity leads to the development of current societal chronic diseases. For decades, however, clinicians and physiologists working in space research have worked separately without taking full awareness of potential strong mutual questioning. This review summarizes the data collected over the last 60 years on metabolic adaptations to bed rest in healthy subjects. Our aim is to provide evidence that supports the hypothesis that physical inactivity per se is one of the primary causes in the development of metabolic inflexibility. This evidence will focus on four main tenants of metabolic inflexiblity: 1) insulin resistance, 2) impaired lipid trafficking and hyperlipidemia, 3) a shift in substrate use toward glucose, and 4) a shift in muscle fiber type and ectopic fat storage. Altogether, this hypothesis places sedentary behaviors upstream on the list of factors involved in metabolic inflexibility, which is considered to be a primary impairment in several metabolic disorders such as obesity, insulin resistance, and type 2 diabetes mellitus.
The protein deacetylase, sirtuin 1 (SIRT1), is a proposed master regulator of exercise-induced mitochondrial biogenesis in skeletal muscle, primarily via its ability to deacetylate and activate peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). To investigate regulation of mitochondrial biogenesis by SIRT1 in vivo, we generated mice lacking SIRT1 deacetylase activity in skeletal muscle (mKO). We hypothesized that deacetylation of PGC-1α and mitochondrial biogenesis in sedentary mice and after endurance exercise would be impaired in mKO mice. Skeletal muscle contractile characteristics were determined in extensor digitorum longus muscle ex vivo. Mitochondrial biogenesis was assessed after 20 days of voluntary wheel running by measuring electron transport chain protein content, enzyme activity, and mitochondrial DNA expression. PGC-1α expression, nuclear localization, acetylation, and interacting protein association were determined following an acute bout of treadmill exercise (AEX) using co-immunoprecipitation and immunoblotting. Contrary to our hypothesis, skeletal muscle endurance, electron transport chain activity, and voluntary wheel running-induced mitochondrial biogenesis were not impaired in mKO versus wild-type (WT) mice. Moreover, PGC-1α expression, nuclear translocation, activity, and deacetylation after AEX were similar in mKO versus WT mice. Alternatively, we made the novel observation that deacetylation of PGC-1α after AEX occurs in parallel with reduced nuclear abundance of the acetyltransferase, general control of amino-acid synthesis 5 (GCN5), as well as reduced association between GCN5 and nuclear PGC-1α. These findings demonstrate that SIRT1 deacetylase activity is not required for exercise-induced deacetylation of PGC-1α or mitochondrial biogenesis in skeletal muscle and suggest that changes in GCN5 acetyltransferase activity may be an important regulator of PGC-1α activity after exercise.
The purpose of this study was to outline the timelines of mitochondrial function, oxidative stress and cytochrome c oxidase complex (COX) biogenesis in cardiac muscle with age, and to evaluate whether and how these age-related changes were attenuated by exercise. ICR/CD-1 mice were treated with pifithrin-μ (PFTμ), sacrificed and studied at different ages; ICR/CD-1 mice at younger or older ages were randomized to endurance treadmill running and sedentary conditions. The results showed that mRNA expression of p53 and its protein levels in mitochondria increased with age in cardiac muscle, accompanied by increased mitochondrial oxidative stress, reduced expression of COX subunits and assembly proteins, and decreased expression of most markers in mitochondrial biogenesis. Most of these age-related changes including p53 activity targeting cytochrome oxidase deficient homolog 2 (SCO2), p53 translocation to mitochondria and COX biogenesis were attenuated by exercise in older mice. PFTμ, an inhibitor blocking p53 translocation to mitochondria, increased COX biogenesis in older mice, but not in young mice. Our data suggest that physical exercise attenuates age-related changes in mitochondrial COX biogenesis and p53 activity targeting SCO2 and mitochondria, and thereby induces antisenescent and protective effects in cardiac muscle.
The coactivator PGC-1alpha mediates key responses of skeletal muscle to motor nerve activity. We show here that neuregulin-stimulated phosphorylation of PGC-1alpha and GA-binding protein (GABP) allows recruitment of PGC-1alpha to the GABP complex and enhances transcription of a broad neuromuscular junction gene program. Since a subset of genes controlled by PGC-1alpha and GABP is dysregulated in Duchenne muscular dystrophy (DMD), we examined the effects of transgenic PGC-1alpha in muscle of mdx mice. These animals show improvement in parameters characteristic of DMD, including muscle histology, running performance, and plasma creatine kinase levels. Thus, control of PGC-1alpha levels in skeletal muscle could represent a novel avenue to prevent or treat DMD.
Current guidelines recommend that "overweight" and "obese" individuals lose weight through engaging in lifestyle modification involving diet, exercise and other behavior change. This approach reliably induces short term weight loss, but the majority of individuals are unable to maintain weight loss over the long term and do not achieve the putative benefits of improved morbidity and mortality. Concern has arisen that this weight focus is not only ineffective at producing thinner, healthier bodies, but may also have unintended consequences, contributing to food and body preoccupation, repeated cycles of weight loss and regain, distraction from other personal health goals and wider health determinants, reduced self-esteem, eating disorders, other health decrement, and weight stigmatization and discrimination. This concern has drawn increased attention to the ethical implications of recommending treatment that may be ineffective or damaging. A growing trans-disciplinary movement called Health at Every Size (HAES) challenges the value of promoting weight loss and dieting behavior and argues for a shift in focus to weight-neutral outcomes. Randomized controlled clinical trials indicate that a HAES approach is associated with statistically and clinically relevant improvements in physiological measures (e.g., blood pressure, blood lipids), health behaviors (e.g., eating and activity habits, dietary quality), and psychosocial outcomes (such as self-esteem and body image), and that HAES achieves these health outcomes more successfully than weight loss treatment and without the contraindications associated with a weight focus. This paper evaluates the evidence and rationale that justifies shifting the health care paradigm from a conventional weight focus to HAES.
Mammals expend energy in many ways, including basic cellular maintenance and repair, digestion, thermoregulation, locomotion, growth and reproduction. These processes can vary tremendously among species and individuals, potentially leading to large variation in daily energy expenditure (DEE). Locomotor energy costs can be substantial for large-bodied species and those with high-activity lifestyles. For humans in industrialized societies, locomotion necessary for daily activities is often relatively low, so it has been presumed that activity energy expenditure and DEE are lower than in our ancestors. Whether this is true and has contributed to a rise in obesity is controversial. In humans, much attention has centered on spontaneous physical activity (SPA) or non-exercise activity thermogenesis (NEAT), the latter sometimes defined so broadly as to include all energy expended due to activity, exclusive of volitional exercise. Given that most people in Western societies engage in little voluntary exercise, increasing NEAT may be an effective way to maintain DEE and combat overweight and obesity. One way to promote NEAT is to decrease the amount of time spent on sedentary behaviours (e.g. watching television). The effects of voluntary exercise on other components of physical activity are highly variable in humans, partly as a function of age, and have rarely been studied in rodents. However, most rodent studies indicate that food consumption increases in the presence of wheels; therefore, other aspects of physical activity are not reduced enough to compensate for the energetic cost of wheel running. Most rodent studies also show negative effects of wheel access on body fat, especially in males. Sedentary behaviours per se have not been studied in rodents in relation to obesity. Several lines of evidence demonstrate the important role of dopamine, in addition to other neural signaling networks (e.g. the endocannabinoid system), in the control of voluntary exercise. A largely separate literature points to a key role for orexins in SPA and NEAT. Brain reward centers are involved in both types of physical activities and eating behaviours, likely leading to complex interactions. Moreover, voluntary exercise and, possibly, eating can be addictive. A growing body of research considers the relationships between personality traits and physical activity, appetite, obesity and other aspects of physical and mental health. Future studies should explore the neurobiology, endocrinology and genetics of physical activity and sedentary behaviour by examining key brain areas, neurotransmitters and hormones involved in motivation, reward and/or the regulation of energy balance.
There are three isoforms of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) mRNA, which promotes mitochondrial biogenesis in skeletal muscles. Compared with PGC-1α-a mRNA, PGC-1α-b or PGC-1α-c mRNA is transcribed by a different exon 1 of the PGC-1α gene. In this study, effects of exercise intensity and 5-aminoimidazole-4-carboxamide-1β-d-ribofuranoside (AICAR) on isoform-specific expressions of PGC-1α were investigated. All isoforms were increased in proportion to exercise intensity of treadmill running (10-30 m/min for 30 min). Preinjection of β₂-adrenergic receptor (AR) antagonist (ICI 118551) inhibited the increase in PGC-1α-b and PGC-1α-c mRNAs, but not the increase in PGC-1α-a mRNA, in response to high-intensity exercise. Although high-intensity exercise activated α2-AMP-activated protein kinase (α2-AMPK) in skeletal muscles, inactivation of α2-AMPK activity did not affect high-intensity exercise-induced mRNA expression of all PGC-1α isoforms, suggesting that activation of α2-AMPK is not mandatory for an increase in PGC-1α mRNA by high-intensity exercise. A single injection in mice of AICAR, an AMPK activator, increased mRNAs of all PGC-1α isoforms. AICAR increased blood catecholamine concentrations, and preinjection of β₂-AR antagonist inhibited the increase in PGC-1α-b and PGC-1α-c mRNAs but not the increase in PGC-1α-a mRNA. Direct exposure of epitrochlearis muscle to AICAR increased PGC-1α-a but not the -b isoform. These data indicate that exercise-induced PGC-1α expression was dependent on the intensity of exercise. Exercise or AICAR injection increased PGC-1α-b and PGC-1α-c mRNAs via β₂-AR activation, whereas high-intensity exercise increased PGC-1α-a expression by a multiple mechanism in which α2-AMPK is one of the signaling pathways.
There is evidence that nitric oxide (NO) is required for the normal increases in skeletal muscle glucose uptake during contraction, but the mechanisms involved have not been elucidated. We examined whether NO regulates glucose uptake during skeletal muscle contractions via cGMP-dependent or cGMP-independent pathways. Isolated extensor digitorum longus (EDL) muscles from mice were stimulated to contract ex vivo, and potential NO signaling pathways were blocked by the addition of inhibitors to the incubation medium. Contraction increased (P < 0.05) NO synthase (NOS) activity (∼40%) and dichlorofluorescein (DCF) fluorescence (a marker of oxidant levels; ∼95%), which was prevented with a NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA), and antioxidants [nonspecific antioxidant, N-acetylcysteine (NAC); thiol-reducing agent, DTT], respectively. L-NMMA and NAC both attenuated glucose uptake during contraction by ∼50% (P < 0.05), and their effects were not additive. Neither the guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one, which prevents the formation of cGMP, the cGMP-dependent protein (PKG) inhibitor Rp-8-bromo-β-phenyl-1,N2-ethenoguanosine 3',5'-cyclic monophosphorothioate sodium salt nor white light, which breaks S-nitrosylated bonds, affects glucose uptake during contraction; however, DTT attenuated (P < 0.05) contraction-stimulated glucose uptake (by 70%). NOS inhibition and antioxidant treatment reduced contraction-stimulated increases in protein S-glutathionylation and tyrosine nitration (P < 0.05), without affecting AMPK or p38 MAPK phosphorylation. In conclusion, we provide evidence to suggest that NOS-derived oxidants regulate skeletal muscle glucose uptake during ex vivo contractions via a cGMP/PKG-, AMPK-, and p38 MAPK-independent pathway. In addition, it appears that NO and ROS may regulate skeletal muscle glucose uptake during contraction through a similar pathway.
The increasing prevalence of obesity and its comorbidities reflects the interaction of genes that favor the storage of excess energy as fat with an environment that provides ad libitum availability of energy-dense foods and encourages an increasingly sedentary lifestyle. Although weight reduction is difficult in and of itself, anyone who has ever lost weight will confirm that it is much harder to keep the weight off once it has been lost. The over 80% recidivism rate to preweight loss levels of body fatness after otherwise successful weight loss is due to the coordinate actions of metabolic, behavioral, neuroendocrine and autonomic responses designed to maintain body energy stores (fat) at a central nervous system-defined 'ideal'. This 'adaptive thermogenesis' creates the ideal situation for weight regain and is operant in both lean and obese individuals attempting to sustain reduced body weights. Much of this opposition to sustained weight loss is mediated by the adipocyte-derived hormone 'leptin'. The multiple systems regulating energy stores and opposing the maintenance of a reduced body weight illustrate that body energy stores in general and obesity in particular are actively 'defended' by interlocking bioenergetic and neurobiological physiologies. Important inferences can be drawn for therapeutic strategies by recognizing obesity as a disease in which the human body actively opposes the 'cure' over long periods of time beyond the initial resolution of symptomatology.
Skeletal muscle contraction increases intracellular ATP turnover, calcium flux, and mechanical stress, initiating signal transduction pathways that modulate peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha)-dependent transcriptional programmes. The purpose of this study was to determine if the intensity of exercise regulates PGC-1alpha expression in human skeletal muscle, coincident with activation of signalling cascades known to regulate PGC-1alpha transcription. Eight sedentary males expended 400 kcal (1674 kj) during a single bout of cycle ergometer exercise on two separate occasions at either 40% (LO) or 80% (HI) of . Skeletal muscle biopsies from the m. vastus lateralis were taken at rest and at +0, +3 and +19 h after exercise. Energy expenditure during exercise was similar between trials, but the high intensity bout was shorter in duration (LO, 69.9 +/- 4.0 min; HI, 36.0 +/- 2.2 min, P < 0.05) and had a higher rate of glycogen utilization (P < 0.05). PGC-1alpha mRNA abundance increased in an intensity-dependent manner +3 h after exercise (LO, 3.8-fold; HI, 10.2-fold, P < 0.05). AMP-activated protein kinase (AMPK) (2.8-fold, P < 0.05) and calcium/calmodulin-dependent protein kinase II (CaMKII) phosphorylation (84%, P < 0.05) increased immediately after HI but not LO. p38 mitogen-activated protein kinase (MAPK) phosphorylation increased after both trials (2.0-fold, P < 0.05), but phosphorylation of the downstream transcription factor, activating transcription factor-2 (ATF-2), increased only after HI (2.4-fold, P < 0.05). Cyclic-AMP response element binding protein (CREB) phosphorylation was elevated at +3 h after both trials (80%, P < 0.05) and class IIa histone deacetylase (HDAC) phosphorylation increased only after HI (2.0-fold, P < 0.05). In conclusion, exercise intensity regulates PGC-1alpha mRNA abundance in human skeletal muscle in response to a single bout of exercise. This effect is mediated by differential activation of multiple signalling pathways, with ATF-2 and HDAC phosphorylation proposed as key intensity-dependent mediators.
The analyses of large epidemiological databases have suggested that infants and children who show catch-up growth, or adiposity rebound at a younger age, are predisposed to the development of obesity, type 2 diabetes and cardiovascular diseases later in life. The pathophysiological mechanisms by which these growth trajectories confer increased risks for these diseases are obscure, but there is compelling evidence that the dynamic process of catch-up growth per se , which often overlaps with adiposity rebound at a younger age, is characterized by hyperinsulinemia and by a disproportionately higher rate in the recovery of body fat than lean tissue (i.e. preferential 'catch-up fat'). This paper first focuses upon the almost ubiquitous nature of this preferential 'catch-up fat' phenotype across the life cycle as a risk factor for obesity and insulin-related complications – not only in infants and children who experienced catch-up growth after earlier fetal or neonatal growth retardation, or after preterm birth, but also in adults who show weight recovery after substantial weight loss owing to famine, disease-cachexia or periodic dieting. It subsequently reviews the evidence indicating that such preferential catch-up fat is primarily driven by energy conservation (thrifty) mechanisms operating via suppressed thermogenesis, with glucose thus spared from oxidation in skeletal muscle being directed towards de novo lipogenesis and storage in white adipose tissue. A molecular–physiological framework is presented which integrates emerging insights into the mechanisms by which this thrifty 'catch-up fat' phenotype crosslinks with early development of insulin and leptin resistance. In the complex interactions between genetic constitution of the individual, programming earlier in life, and a subsequent lifestyle of energy dense foods and low physical activity, this thrifty 'catch-up fat' phenotype – which probably evolved to increase survival capacity in a hunter–gatherer lifestyle of periodic food shortages – is a central event in growth trajectories to obesity and to diseases that cluster into the insulin resistance (metabolic) syndrome.
Catch-up growth, a risk factor for later type 2 diabetes, is characterized by hyperinsulinemia, accelerated body-fat recovery (catch-up fat), and enhanced glucose utilization in adipose tissue. Our objective was to characterize the determinants of enhanced glucose utilization in adipose tissue during catch-up fat.
White adipose tissue morphometry, lipogenic capacity, fatty acid composition, insulin signaling, in vivo glucose homeostasis, and insulinemic response to glucose were assessed in a rat model of semistarvation-refeeding. This model is characterized by glucose redistribution from skeletal muscle to adipose tissue during catch-up fat that results solely from suppressed thermogenesis (i.e., without hyperphagia).
Adipose tissue recovery during the dynamic phase of catch-up fat is accompanied by increased adipocyte number with smaller diameter, increased expression of genes for adipogenesis and de novo lipogenesis, increased fatty acid synthase activity, increased proportion of saturated fatty acids in triglyceride (storage) fraction but not in phospholipid (membrane) fraction, and no impairment in insulin signaling. Furthermore, it is shown that hyperinsulinemia and enhanced adipose tissue de novo lipogenesis occur concomitantly and are very early events in catch-up fat.
These findings suggest that increased adipose tissue insulin stimulation and consequential increase in intracellular glucose flux play an important role in initiating catch-up fat. Once activated, the machinery for lipogenesis and adipogenesis contribute to sustain an increased insulin-stimulated glucose flux toward fat storage. Such adipose tissue plasticity could play an active role in the thrifty metabolism that underlies glucose redistribution from skeletal muscle to adipose tissue.
Type 2 diabetes is characterized by fasting hyperglycemia, secondary to hepatic insulin resistance and increased glucose production. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a transcriptional coactivator that is thought to control adaptive responses to physiological stimuli. In liver, PGC-1α expression is induced by fasting, and this effect promotes gluconeogenesis. To examine whether PGC-1α is involved in the pathogenesis of hepatic insulin resistance, we generated transgenic (TG) mice with whole body overexpression of human PGC-1α and evaluated glucose homeostasis with a euglycemic-hyperinsulinemic clamp. PGC-1α was moderately (∼2-fold) overexpressed in liver, skeletal muscle, brain, and heart of TG mice. In liver, PGC-1α overexpression resulted in increased expression of hepatocyte nuclear factor-4α and the gluconeogenic enzymes phosphoenolpyruvate carboxykinase and glucose-6- phosphatase. PGC-1α overexpression caused hepatic insulin resistance, manifested by higher glucose production and diminished insulin suppression of gluconeogenesis. Paradoxically, PGC-1α overexpression improved muscle insulin sensitivity, as evidenced by elevated insulin-stimulated Akt phosphorylation and peripheral glucose disposal. Content of myoglobin and troponin I slow protein was increased in muscle of TG mice, indicating fiber-type switching. PGC-1α overexpression also led to lower reactive oxygen species production by mitochondria and reduced IKK/IκB signaling in muscle. Feeding a high-fat diet to TG mice eliminated the increased muscle insulin sensitivity. The dichotomous effect of PGC-1α overexpression in liver and muscle suggests that PGC-1α is a fuel gauge that couples energy demands (muscle) with the corresponding fuel supply (liver). Thus, under conditions of physiological stress (i.e., prolonged fast and exercise training), increased hepatic glucose production may help sustain glucose utilization in peripheral tissues.
AMPK (AMP-activated protein kinase) is a phylogenetically conserved fuel-sensing enzyme that is present in all mammalian cells. During exercise, it is activated in skeletal muscle in humans, and at least in rodents, also in adipose tissue, liver and perhaps other organs by events that increase the AMP/ATP ratio. When activated, AMPK stimulates energy-generating processes such as glucose uptake and fatty acid oxidation and decreases energy-consuming processes such as protein and lipid synthesis. Exercise is perhaps the most powerful physiological activator of AMPK and a unique model for studying its many physiological roles. In addition, it improves the metabolic status of rodents with a metabolic syndrome phenotype, as does treatment with AMPK-activating agents; it is therefore tempting to attribute the therapeutic benefits of regular physical activity to activation of AMPK. Here we review the acute and chronic effects of exercise on AMPK activity in skeletal muscle and other tissues. We also discuss the potential role of AMPK activation in mediating the prevention and treatment by exercise of specific disorders associated with the metabolic syndrome, including Type 2 diabetes and Alzheimer's disease.
Mitochondrial biogenesis occurs in response to increased cellular ATP demand. The mitochondrial electron transport chain requires molecular oxygen to produce ATP. Thus, increased ATP generation after mitochondrial biogenesis results in increased oxygen demand that must be matched by a corresponding increase in oxygen supply. We found that overexpression of peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha), which increases mitochondrial biogenesis in primary skeletal muscle cells, leads to increased expression of a cohort of genes known to be regulated by the dimeric hypoxia-inducible factor (HIF), a master regulator of the adaptive response to hypoxia. PGC-1alpha-dependent induction of HIF target genes under physiologic oxygen concentrations is not through transcriptional coactivation of HIF or up-regulation of HIF-1alpha mRNA but through HIF-1alpha protein stabilization. It occurs because of intracellular hypoxia as a result of increased oxygen consumption after mitochondrial biogenesis. Thus, we propose that at physiologic oxygen concentrations, PGC-1alpha is coupled to HIF signaling through the regulation of intracellular oxygen availability, allowing cells and tissues to match increased oxygen demand after mitochondrial biogenesis with increased oxygen supply.
From a cell signaling perspective, short-duration intense muscular work is typically associated with resistance training and linked to pathways that stimulate growth. However, brief repeated sessions of sprint or high-intensity interval exercise induce rapid phenotypic changes that resemble traditional endurance training. We tested the hypothesis that an acute session of intense intermittent cycle exercise would activate signaling cascades linked to mitochondrial biogenesis in human skeletal muscle. Biopsies (vastus lateralis) were obtained from six young men who performed four 30-s "all out" exercise bouts interspersed with 4 min of rest (<80 kJ total work). Phosphorylation of AMP-activated protein kinase (AMPK; subunits alpha1 and alpha2) and the p38 mitogen-activated protein kinase (MAPK) was higher (P <or= 0.05) immediately after bout 4 vs. preexercise. Peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha) mRNA was increased approximately twofold above rest after 3 h of recovery (P <or= 0.05); however, PGC-1alpha protein content was unchanged. In contrast, phosphorylation of protein kinase B/Akt (Thr(308) and Ser(473)) tended to decrease, and downstream targets linked to hypertrophy (p70 ribosomal S6 kinase and 4E binding protein 1) were unchanged after exercise and recovery. We conclude that signaling through AMPK and p38 MAPK to PGC-1alpha may explain in part the metabolic remodeling induced by low-volume intense interval exercise, including mitochondrial biogenesis and an increased capacity for glucose and fatty acid oxidation.
Peroxisome proliferator-activated receptor-γ coactivator (PGC)-1α has been shown to play critical roles in regulating mitochondria biogenesis, respiration, and muscle oxidative phenotype. Furthermore, reductions in the expression of PGC-1α in muscle have been implicated in the pathogenesis of type 2 diabetes. To determine the effect of increased muscle-specific PGC-1α expression on muscle mitochondrial function and glucose and lipid metabolism in vivo, we examined body composition, energy balance, and liver and muscle insulin sensitivity by hyperinsulinemic-euglycemic clamp studies and muscle energetics by using ³¹P magnetic resonance spectroscopy in transgenic mice. Increased expression of PGC-1α in muscle resulted in a 2.4-fold increase in mitochondrial density, which was associated with an ≈60% increase in the unidirectional rate of ATP synthesis. Surprisingly, there was no effect of increased muscle PGC-1α expression on whole-body energy expenditure, and PGC-1α transgenic mice were more prone to fat-induced insulin resistance because of decreased insulin-stimulated muscle glucose uptake. The reduced insulin-stimulated muscle glucose uptake could most likely be attributed to a relative increase in fatty acid delivery/triglyceride reesterfication, as reflected by increased expression of CD36, acyl-CoA:diacylglycerol acyltransferase1, and mitochondrial acyl-CoA:glycerol-sn-3-phosphate acyltransferase, that may have exceeded mitochondrial fatty acid oxidation, resulting in increased intracellular lipid accumulation and an increase in the membrane to cytosol diacylglycerol content. This, in turn, caused activation of PKCθ, decreased insulin signaling at the level of insulin receptor substrate-1 (IRS-1) tyrosine phosphorylation, and skeletal muscle insulin resistance.
• diacylglycerol
• fatty acid oxidation
• insulin resistance
• magnetic resonance spectroscopy
• mitochondria
AMP-activated protein kinase (AMPK) is a key signaling protein in the regulation of skeletal muscle glucose uptake, but its role in mediating contraction-induced glucose transport is still debated. The effect of contraction on glucose transport is impaired in EDL muscle of transgenic mice expressing a kinase-dead, dominant negative form of the AMPKalpha(2) subunit (KD-AMPKalpha(2) mice). However, maximal force production is reduced in this muscle, raising the possibility that the defect in glucose transport was due to a secondary decrease in force production and not impaired AMPKalpha(2) activity. Generation of force-frequency curves revealed that muscle force production is matched between wild-type (WT) and KD-AMPKalpha(2) mice at frequencies < or =50 Hz. Moreover, AMPK activation is already maximal at 50 Hz in muscles of WT mice. When EDL muscles from WT mice were stimulated at a frequency of 50 Hz for 2 min (200-ms train, 1/s, 30 volts), contraction caused an approximately 3.5-fold activation of AMPKalpha(2) activity and an approximately 2-fold stimulation of glucose uptake. Conversely, whereas force production was similar in EDL of KD-AMPKalpha(2) animals, no effect of contraction was observed on AMPKalpha(2) activity, and glucose uptake stimulation was reduced by 50% (P < 0.01) As expected, 5-aminoimidazole-4-carboxamide-1-beta-d-ribofuranosyl 5'-monophosphate (AICAR) caused a 2.3-fold stimulation of AMPKalpha(2) activity and a 1.7-fold increase in glucose uptake in EDL from WT mice, whereas no effect was detected in muscle from KD-AMPKalpha(2) mice. These data demonstrate that AMPK activation is essential for both AICAR and submaximal contraction-induced glucose transport in skeletal muscle but that AMPK-independent mechanisms are also involved.
The transcriptional coactivator PPARgamma coactivator 1alpha (PGC-1alpha) is a strong activator of mitochondrial biogenesis and oxidative metabolism. While expression of PGC-1alpha and many of its mitochondrial target genes are decreased in the skeletal muscle of patients with type 2 diabetes, no causal relationship between decreased PGC-1alpha expression and abnormal glucose metabolism has been established. To address this question, we generated skeletal muscle-specific PGC-1alpha knockout mice (MKOs), which developed significantly impaired glucose tolerance but showed normal peripheral insulin sensitivity. Surprisingly, MKOs had expanded pancreatic beta cell mass, but markedly reduced plasma insulin levels, in both fed and fasted conditions. Muscle tissue from MKOs showed increased expression of several proinflammatory genes, and these mice also had elevated levels of the circulating IL-6. We further demonstrated that IL-6 treatment of isolated mouse islets suppressed glucose-stimulated insulin secretion. These data clearly illustrate a causal role for muscle PGC-1alpha in maintenance of glucose homeostasis and highlight an unexpected cytokine-mediated crosstalk between skeletal muscle and pancreatic islets.
In eukaryotes, cellular and systemic metabolism is
primarily controlled by mitochondrial activity. The peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) is an important regulator of mitochondrial biogenesis and function. Furthermore, PGC-1alpha controls many of the phenotypic adaptations of oxidative tissues to external and internal perturbations. By contrast, dysregulated metabolic plasticity is involved in the etiology of numerous diseases. Accordingly, modulation of PGC-1alpha levels and activity has recently been proposed as a therapeutic option for several pathologies. However, pharmacological interventions aimed at PGC-1alpha have to overcome inherent limitations of targeting a coactivator protein. Here, I focus on the recent breakthroughs in the identification of physiological and pathophysiological contexts involving PGC-1alpha. In addition, perspectives regarding the therapeutic importance of PGC-1alpha controlled cellular and systemic metabolism are outlined.
Peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) is considered to play a pivotal role in the exercise-induced metabolic adaptation of skeletal muscle. Although the oxidized form of nicotinamide adenine dinucloetide (NAD+)-dependent histone deacetylase SIRT1 has been shown to mediate PGC-1α–induced metabolic adaptation, the effect of endurance exercise on the SIRT1 protein remains to be elucidated. The purposes of this study were (1) to investigate the distribution of SIRT1 and PGC-1α proteins in skeletal muscle and (2) to examine the effects of acute endurance exercise and low- or high-intensity exercise training on SIRT1 and PGC-1α protein expressions and on the metabolic components in rat skeletal muscle. Both the SIRT1 and PGC-1α proteins preferentially accumulate in red oxidative muscles. Acute endurance exercise on a motor-driven treadmill (20 m/min, 18.5% incline, 45 minutes) increases the PGC-1α protein expression at 18 hours after exercise and the SIRT1 protein expression at 2 hours after exercise in the soleus muscle. In the training experiment, the rats were divided into control, low-intensity (20 m/min, 18.5% incline, 90 min/d), and high-intensity (30 m/min, 18.5% incline, 60 min/d) training groups. After 14 days of training, the SIRT1 and PGC-1α proteins, hexokinase activity, mitochondrial proteins and enzyme activities, and glucose transporter 4 protein in the soleus muscle were increased by both trainings. In the plantaris muscle, SIRT1, hexokinase activity, mitochondrial proteins and enzyme activities, and glucose transporter 4 were increased by high-intensity training whereas the PGC-1α was not. These results suggest that endurance exercise increases the skeletal muscle SIRT1 protein content. In addition, the findings also raise the possibility that the SIRT1 protein expression may play a potentially important role in such adaptations, whereas an increase in the PGC-1α protein expression is not necessary for such adaptations.
Cardiac mitochondrial function is altered in a variety of inherited and acquired cardiovascular diseases. Recent studies have identified the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) as a regulator of mitochondrial function in tissues specialized for thermogenesis, such as brown adipose. We sought to determine whether PGC-1 controlled mitochondrial biogenesis and energy-producing capacity in the heart, a tissue specialized for high-capacity ATP production. We found that PGC-1 gene expression is induced in the mouse heart after birth and in response to short-term fasting, conditions known to increase cardiac mitochondrial energy production. Forced expression of PGC-1 in cardiac myocytes in culture induced the expression of nuclear and mitochondrial genes involved in multiple mitochondrial energy-transduction/energy-production pathways, increased cellular mitochondrial number, and stimulated coupled respiration. Cardiac-specific overexpression of PGC-1 in transgenic mice resulted in uncontrolled mitochondrial proliferation in cardiac myocytes leading to loss of sarcomeric structure and a dilated cardiomyopathy. These results identify PGC-1 as a critical regulatory molecule in the control of cardiac mitochondrial number and function in response to energy demands.
Peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α) is a key nuclear receptor co-activator for mitochondrial biogenesis. Here we report that overexpression of PGC-1α in skeletal muscles increased mitochondrial number and caused atrophy of skeletal muscle, especially type 2B fiber-rich muscles (gastrocnemius, quadriceps, and plantaris). Muscle atrophy became evident at 25 weeks of age, and a portion of the muscle was replaced by adipocytes. Mice showed increased energy expenditure and reduced body weight; thyroid hormone levels were normal. Mitochondria exhibited normal respiratory chain activity per mitochondrion; however, mitochondrial respiration was not inhibited by an ATP synthase inhibitor, oligomycin, clearly indicating that oxidative phosphorylation was uncoupled. Accordingly, ATP content in gastrocnemius was markedly reduced. A similar phenotype is observed in Luft's disease, a mitochondrial disorder that involves increased uncoupling of respiration and muscle atrophy. Our results indicate that overexpression of PGC-1α in skeletal muscle increases not only mitochondrial biogenesis but also uncoupling of respiration, resulting in muscle atrophy.
Investigations of biological programs that are controlled by gene transcription have mainly studied the regulation of tran- scription factors. However, there are examples in which the primary focus of biological regulation is at the level of a tran- scriptional coactivator. We have reviewed here the molecular mechanisms and biological programs controlled by the tran- scriptional coactivator peroxisome proliferator-activated re- ceptor- coactivator 1 (PGC-1). Key cellular signals that control energy and nutrient homeostasis, such as cAMP and cytokine pathways, strongly activate PGC-1. Once PGC-1 is activated, it powerfully induces and coordinates gene expres- sion that stimulates mitochondrial oxidative metabolism in brown fat, fiber-type switching in skeletal muscle, and mul- tiple aspects of the fasted response in liver. The regulation of these metabolic and cell fate decisions by PGC-1 is achieved through specific interaction with a variety of tran- scription factors such as nuclear hormone receptors, nuclear respiratory factors, and muscle-specific transcription factors. PGC-1 therefore constitutes one of the first and clearest ex- amples in which biological programs are chiefly regulated by a transcriptional coactivator in response to environmental stimuli. Finally, PGC-1's control of energy homeostasis sug- gests that it could be a target for antiobesity or diabetes drugs. (Endocrine Reviews 24: 78 -90, 2003)
Reactive oxygen species (ROS) play an important role in normal signaling events and excessive ROS are associated with many pathological conditions. The amount of ROS in cells is dependent on both the production of ROS by the mitochondrial electron transport chain and their removal by ROS-detoxifying enzymes. The peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) is a master regulator of mitochondrial functions and a key regulator of the ROS-detoxifying program. However, the impact of PGC-1α on the topology and rate of superoxide production by the mitochondrial electron transport chain is not known. We report here, using mitochondria from muscle creatine kinase-PGC-1α transgenic mice, that PGC-1α does not affect the topology of ROS production, but increases the capacity of complexes I and III to generate ROS. These changes are associated with increased mitochondrial respiration and content of respiratory chain complexes. When normalizing ROS production to mitochondrial respiration, we find that PGC-1α preserves the percentage of free radical leak by the electron transport chain. Together, these data demonstrate that PGC-1α regulates the intrinsic properties of mitochondria in such a way as to preserve a tight coupling between mitochondrial respiration and ROS production.
Regular endurance exercise remodels skeletal muscle, largely through the peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α). PGC-1α promotes fiber type switching and resistance to fatigue. Intracellular calcium levels might play a role in both adaptive phenomena, yet a role for PGC-1α in the adaptation of calcium handling in skeletal muscle remains unknown. Using mice with transgenic overexpression of PGC-1α, we now investigated the effect of PGC-1α on calcium handling in skeletal muscle. We demonstrate that PGC-1α induces a quantitative reduction in calcium release from the sarcoplasmic reticulum by diminishing the expression of calcium-releasing molecules. Concomitantly, maximal muscle force is reduced in vivo and ex vivo. In addition, PGC-1α overexpression delays calcium clearance from the myoplasm by interfering with multiple mechanisms involved in calcium removal, leading to higher myoplasmic calcium levels following contraction. During prolonged muscle activity, the delayed calcium clearance might facilitate force production in mice overexpressing PGC-1α. Our results reveal a novel role of PGC-1α in altering the contractile properties of skeletal muscle by modulating calcium handling. Importantly, our findings indicate PGC-1α to be both down- as well as upstream of calcium signaling in this tissue. Overall, our findings suggest that in the adaptation to chronic exercise, PGC-1α reduces maximal force, increases resistance to fatigue, and drives fiber type switching partly through remodeling of calcium transients, in addition to promoting slow-type myofibrillar protein expression and adequate energy supply.
It has been known for more than 4 decades that exercise causes increases in skeletal muscle mitochondrial enzyme content and activity (i.e., mitochondrial biogenesis). Increasing evidence now suggests that exercise can induce mitochondrial biogenesis in a wide range of tissues not normally associated with the metabolic demands of exercise. Perturbations in mitochondrial content and (or) function have been linked to a wide variety of diseases, in multiple tissues, and exercise may serve as a potent approach by which to prevent and (or) treat these pathologies. In this context, the purpose of this review is to highlight the effects of exercise, and the underlying mechanisms therein, on the induction of mitochondrial biogenesis in skeletal muscle, adipose tissue, liver, brain, and kidney.
Adaptive thermogenesis is an important component of energy homeostasis and a metabolic defense against obesity. We have cloned a novel transcriptional coactivator of nuclear receptors, termed PGC-1, from a brown fat cDNA library. PGC-1 mRNA expression is dramatically elevated upon cold exposure of mice in both brown fat and skeletal muscle, key thermogenic tissues. PGC-1 greatly increases the transcriptional activity of PPARgamma and the thyroid hormone receptor on the uncoupling protein (UCP-1) promoter. Ectopic expression of PGC-1 in white adipose cells activates expression of UCP-1 and key mitochondrial enzymes of the respiratory chain, and increases the cellular content of mitochondrial DNA. These results indicate that PGC-1 plays a key role in linking nuclear receptors to the transcriptional program of adaptive thermogenesis.
The function of uncoupling protein 3 (UCP3) is still not established. Mitochondrial uncoupling, control of ROS production, protection against lipotoxicity and protection against oxidative stress are functions classically discussed. To establish a role for UCP3 in these functions, we have here used UCP3 (-/-) mice, backcrossed for 10 generations on a C57Bl/6 background. In isolated skeletal muscle mitochondria, we examined uncoupled respiration, both unstimulated and in the presence of fatty acids. We did not observe any difference between mitochondria from wildtype and UCP3 (-/-) mice. We measured H(2)O(2) production rate and respiration rate under reactive oxygen species-generating conditions (succinate without rotenone) but found no effect of UCP3. We tested two models of acute lipotoxicity-fatty acid-induced oxidative inhibition and fatty acid-induced swelling-but did not observe any protective effect of UCP3. We examined oxidative stress by quantifying 4-hydroxynonenal protein adducts and protein carbonyls in the mitochondria-but did not observe any protective effect of UCP3. We conclude that under the experimental conditions tested here, we find no evidence for the function of UCP3 being basal or induced uncoupling, regulation of ROS production, protection against acute lipotoxicity or protection against oxidative damage.
Chronic heart failure often results in catabolic muscle wasting, exercise intolerance, and death. Oxidative muscles, which have greater expression of the metabolic master gene peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) and its target genes, are more resistant to catabolic wasting than are glycolytic muscles; however, the underlying mechanism is unknown. To determine the functional role of PGC-1α in oxidative phenotype-associated protection, skeletal muscle-specific PGC-1α transgenic mice were crossbred with cardiac-specific calsequestrin transgenic mice, a genetic model of chronic heart failure. PGC-1α overexpression in glycolytic muscles significantly attenuated catabolic muscle wasting induced by chronic heart failure. In addition to inactivation of forkhead transcription factor signaling through enhanced Akt/protein kinase B expression, in glycolytic muscles, PGC-1α overexpression led to enhanced expression of inducible nitric oxide synthase and endothelial nitric oxide synthase, production of nitric oxide, and expression of antioxidant enzyme including superoxide dismutases (SOD1, SOD2, and SOD3) and catalase, and reduced oxidative stress. These findings suggest that PGC-1α protects muscle from catabolic wasting in chronic heart failure through enhanced nitric oxide antioxidant defenses and inhibition of the forkhead transcription factor signaling pathways.
In the past, the role of physical activity as a life-style modulating factor has been considered as that of a tool to balance energy intake. Although it is important to avoid obesity, physical inactivity should be discussed in a much broader context. There is accumulating epidemiological evidence that a physically active life plays an independent role in the protection against type 2 diabetes, cardiovascular diseases, cancer, dementia and even depression. For most of the last century, researchers sought a link between muscle contraction and humoral changes in the form of an 'exercise factor', which could be released from skeletal muscle during contraction and mediate some of the exercise-induced metabolic changes in other organs such as the liver and the adipose tissue. We have suggested that cytokines or other peptides that are produced, expressed and released by muscle fibres and exert autocrine, paracrine or endocrine effects should be classified as 'myokines'. Given that skeletal muscle is the largest organ in the human body, our discovery that contracting skeletal muscle secretes proteins sets a novel paradigm: skeletal muscle is an endocrine organ producing and releasing myokines, which work in a hormone-like fashion, exerting specific endocrine effects on other organs. Other myokines work via paracrine mechanisms, exerting local effects on signalling pathways involved in muscle metabolism. It has been suggested that myokines may contribute to exercise-induced protection against several chronic diseases.
The global incidence and prevalence of obesity continue to increase, with the fastest rate of increase in the developing world. Obesity is associated with many chronic diseases including type 2 diabetes, cardiovascular disease and some cancers. Weight loss can reduce the risk of developing these diseases and can be achieved by means of surgery, pharmacotherapy and lifestyle interventions. Lifestyle interventions for prevention and treatment of obesity include diet, exercise and psychological interventions. All lifestyle interventions have a modest but significant effect on weight loss, but there is little evidence to indicate that any one intervention is more effective. There is evidence of an additive effect for adjunct therapy, and the combination of diet, exercise and behavioural interventions appears to be most effective for both the prevention and treatment of obesity.
Exercise induces a pleiotropic adaptive response in skeletal muscle, largely through peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). PGC-1α enhances lipid oxidation and thereby provides energy for sustained muscle contraction. Its potential implication in promoting muscle refueling remains unresolved, however. Here, we investigated a possible role of elevated PGC-1α levels in skeletal muscle lipogenesis in vivo and the molecular mechanisms that underlie PGC-1α-mediated de novo lipogenesis. To this end, we studied transgenic mice with physiological overexpression of PGC-1α and human muscle biopsies pre- and post-exercise. We demonstrate that PGC-1α enhances lipogenesis in skeletal muscle through liver X receptor α-dependent activation of the fatty acid synthase (FAS) promoter and by increasing FAS activity. Using chromatin immunoprecipitation, we establish a direct interaction between PGC-1α and the liver X receptor-responsive element in the FAS promoter. Moreover, we show for the first time that increased glucose uptake and activation of the pentose phosphate pathway provide substrates for RNA synthesis and cofactors for de novo lipogenesis. Similarly, we observed increased lipogenesis and lipid levels in human muscle biopsies that were obtained post-exercise. Our findings suggest that PGC-1α coordinates lipogenesis, intramyocellular lipid accumulation, and substrate oxidation in exercised skeletal muscle in vivo.
Regular exercise promotes favorable structural and metabolic adaptations, especially in the skeletal muscle, to boost endurance and cardiovascular health. These changes are driven by a network of incompletely understood molecular pathways that trigger transcriptional remodeling of the skeletal muscle. In this article, we describe recent advances in the understanding of the key components of this circuitry [namely peroxisome proliferator activator receptor delta (PPARdelta), adenosine monophosphate (AMP)-activated protein kinase (AMPK), silent information regulator two protein 1 (SIRT1), and peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha)] that govern aerobic transformation of the skeletal muscles. We also discuss recent discoveries that raise the possibility of synthetically mimicking exercise with pathway-specific drugs to improve aerobic capacity and, in turn, health.
2-Methoxyoestradiol (2-ME) is an oestrogen derivative that inhibits superoxide dismutase (which converts superoxide anions to H(2)O(2)). Since reactive oxygen species have been implicated in glucose transport, we determined the effect of 2-ME on glucose transport in skeletal muscle. Experiments were performed on isolated mouse extensor digitorum longus (EDL, glycolytic, fast-twitch) muscle. Glucose uptake was measured using 2-deoxy-d-[1,2-(3)H]glucose. 2-Methoxyoestradiol (50 microm) reduced glucose uptake induced by insulin, contraction and hypoxia by approximately 60%. Exogenous H(2)O(2) activated glucose uptake, and this effect was also blocked by 2-ME, demonstrating that 2-ME was exerting its inhibitory effect on glucose uptake at a site other than superoxide dismutase. When glucose uptake was stimulated by insulin, followed by addition of 2-ME, there was also an attenuation of the effect of insulin (approximately 60%). Moreover, basal glucose uptake was decreased by 2-ME (approximately 50%). In contrast, insulin-mediated translocation of glucose transporter type 4 protein to the plasma membrane was not affected by 2-ME. Similar results were obtained in soleus (oxidative, slow-twitch) muscle. In conclusion, 2-ME appears to decrease glucose transport in skeletal muscle by directly interfering with the function of glucose transport proteins in surface membranes.
The peroxisome proliferator-activated receptor-γ (PPARγ) coactivator-1α (PGC-1α) is a major regulator of exercise-induced phenotypic adaptation and substrate utilization. We provide an overview of 1) the role of PGC-1α in exercise-mediated muscle adaptation and 2) the possible insulin-sensitizing role of PGC-1α. To these ends, the following questions are addressed. 1) How is PGC-1α regulated, 2) what adaptations are indeed dependent on PGC-1α action, 3) is PGC-1α altered in insulin resistance, and 4) are PGC-1α-knockout and -transgenic mice suitable models for examining therapeutic potential of this coactivator? In skeletal muscle, an orchestrated signaling network, including Ca 2+-dependent pathways, reactive oxygen species (ROS), nitric oxide (NO), AMP-dependent protein kinase (AMPK), and p38 MAPK, is involved in the control of contractile protein expression, angiogenesis, mitochondrial biogenesis, and other adaptations. However, the p38γ MAPK/PGC-1α regulatory axis has been con-firmed to be required for exercise-induced angiogenesis and mitochondrial biogenesis but not for fiber type transformation. With respect to a potential insulinsensitizing role of PGC-1α, human studies on type 2 diabetes suggest that PGC-1α and its target genes are only modestly downregulated (≤34%). However, studies in PGC-1α-knockout or PGC-1α-transgenic mice have provided unexpected anomalies, which appear to suggest that PGC-1α does not have an insulin-sensitizing role. In contrast, a modest (∼25%) upregulation of PGC-1α, within physiological limits, does improve mitochondrial biogenesis, fatty acid oxidation, and insulin sensitivity in healthy and insulin-resistant skeletal muscle. Taken altogether, there is substantial evidence that the p38γ MAPK-PGC-1α regulatory axis is critical for exercise-induced metabolic adaptations in skeletal muscle, and strategies that upregulate PGC-1α, within physiological limits, have revealed its insulin-sensitizing effects.
Exercise triggers a pleiotropic response in skeletal muscle, which results in a profound remodeling of this tissue. Physical activity-dependent muscle fiber plasticity is regulated by a number of distinct signaling pathways. Even though most of these pathways are activated by different stimuli and in a temporally and spatially separated manner during exercise, many of the major signal transduction events converge on the peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α) by post-translationally modifying the PGC-1α protein, modulating PGC-1α gene expression or both. In turn, depending on the cellular context, PGC-1α regulates specific gene programs. Ultimately, PGC-1α modulates most of the transcriptional adaptations of skeletal muscle to exercise. In this review, the regulation and function of this pivotal transcriptional coactivator in muscle are discussed.
Dysregulation of fatty acid oxidation (FAO) is recognized as important in the pathophysiology of obesity and insulin resistance (IR). However, demonstrating FAO defects in vivo in humans has entailed complex and invasive methodologies. Recently, the identification of genetic blocks in FAO has been vastly simplified by using tandem mass spectrometry (MS/MS) of dried bloodspots to specify acylcarnitine (AcylCN) alterations characteristic for each disorder. This technology has recently been applied to examine FAO alterations in human and animal models of obesity and type 2 diabetes mellitus (T2DM). This study focused on characterizing AcylCN profiles in human plasma from individuals with obesity and T2DM during fasting and insulin-stimulated conditions. Following an overnight fast, plasma was obtained from lean (n = 12), obese nondiabetic (n = 14), and T2DM (n = 10) participants and analyzed for AcylCN using MS/MS. Plasma samples were also obtained at the end of a 4-h insulin-stimulated euglycemic clamp. In obesity and T2DM, long-chain AcylCNs were similarly significantly increased in the fasted state; free-CN levels were also elevated. Additionally, T2DM subjects of comparable BMI had increased short- and medium-chain AcylCNs, both saturated and hydroxy, as well as increased C(4)-dicarboxylcarnitine (C(4)DC-CN) that correlated with an index of poor glycemic control (HbA(1c); r = 0.74; P < 0.0001). Insulin infusion reduced all species of plasma AcylCN but this reduction was blunted in T2DM. Plasma long-chain AcylCN species are increased in obesity and T2DM, suggesting that more fatty acids can enter mitochondria. In T2DM, many shorter species accumulate, suggesting that they have a generalized complex oxidation defect.
Lifestyle interventions in a healthcare setting are effective for weight loss, but it is unclear whether more expensive interventions result in more weight loss. Our objective was to explore the relationship between intervention costs and effectiveness in a systematic review of randomized trials.
Intervention studies were selected from 14 reviews and from a systematic MEDLINE-search. Studies had to contain a dietary and a physical activity component and report data on measured weight loss in healthy Caucasian overweight adults. Intervention costs were calculated in a standardized way. The association between costs and percentage weight loss after 1 year was assessed using regression analysis.
Nineteen original studies describing 31 interventions were selected. The relationship between weight loss and intervention costs was best described by an asymptotic regression model, which explained 47% of the variance in weight loss. A clinically relevant weight loss of 5% was already observed in interventions of approximately €110. Results were similar in an intention-to-treat analysis.
In conclusion, lifestyle interventions in health care for overweight adults are relatively cheap and higher intervention costs are associated with more weight loss, although the effect of costs on weight loss levels off with growing costs.
The increasing prevalence of type 2 diabetes throughout the world is now recognized as a major health problem. A growing segment of the population has impaired glucose tolerance (IGT), which is a strong predictor of progression to type 2 diabetes. Further, 24% of Americans now meet the criteria for the metabolic syndrome, a risk factor for both type 2 diabetes and cardiovascular disease (CVD). The diabetes epidemic is associated with changes in lifestyle-most notably increased energy intake, changes in diet composition and decreased levels of physical activity-and the development of overweight and obesity. This review examines the effects of several intensive lifestyle intervention trials on the risk of diabetes and CVD among high-risk populations. Common features of these lifestyle interventions are dietary modification, weight loss and increased physical activity. These trials indicate that lifestyle modification is effective in decreasing the progression from IGT to type 2 diabetes and reducing CVD risk factors. However, the effectiveness of lifestyle interventions for reductions in CVD events has yet to be determined.
In eukaryotes, cellular and systemic metabolism is primarily controlled by mitochondrial activity. The peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) is an important regulator of mitochondrial biogenesis and function. Furthermore, PGC-1alpha controls many of the phenotypic adaptations of oxidative tissues to external and internal perturbations. By contrast, dysregulated metabolic plasticity is involved in the etiology of numerous diseases. Accordingly, modulation of PGC-1alpha levels and activity has recently been proposed as a therapeutic option for several pathologies. However, pharmacological interventions aimed at PGC-1alpha have to overcome inherent limitations of targeting a coactivator protein. Here, I focus on the recent breakthroughs in the identification of physiological and pathophysiological contexts involving PGC-1alpha. In addition, perspectives regarding the therapeutic importance of PGC-1alpha-controlled cellular and systemic metabolism are outlined.
Alternatives to the canonical insulin-stimulated pathway for glucose uptake are exercise- and exogenous reactive oxygen species (ROS)-stimulated glucose uptake. We proposed a model wherein mechanical loading, i.e. stretch, stimulates production of ROS to activate AMP-activated kinase (AMPK) to increase glucose uptake. Immunoblotting was used to measure protein phosphorylation; the fluorochrome probe 2'7'-dichlorofluorescin diacetate was used to measure cytosolic oxidant activity and 2-deoxy-d[1,2-(3)H]glucose was used to measure glucose uptake. The current studies demonstrate that stretch increases ROS, AMPKalpha phosphorylation and glucose transport in murine extensor digitorum longus (EDL) muscle (+121%, +164% and +184%, respectively; P < 0.05). We also demonstrate that stretch-induced glucose uptake persists in transgenic mice expressing an inactive form of the AMPKalpha2 catalytic subunit in skeletal muscle (+173%; P < 0.05). MnTBAP, a superoxide dismutase (SOD) mimetic, N-acteyl cysteine (NAC), a non-specific antioxidant, ebselen, a glutathione mimetic, or combined SOD plus catalase (ROS-selective scavengers) all decrease stretch-stimulated glucose uptake (P < 0.05) without changing basal uptake (P > 0.16). We also demonstrate that stretch-stimulated glucose uptake persists in the presence of the phosphatidylinositol 3-kinase (PI3-K) inhibitors wortmannin and LY294001 (P < 0.05) but is diminished by the p38-MAPK inhibitors SB203580 and A304000 (P > 0.99). These data indicate that stretch-stimulated glucose uptake in skeletal muscle is mediated by a ROS- and p38 MAPK-dependent mechanism that appears to be AMPKalpha2- and PI3-K-independent.
We projected future prevalence and BMI distribution based on national survey data (National Health and Nutrition Examination Study) collected between 1970s and 2004. Future obesity-related health-care costs for adults were estimated using projected prevalence, Census population projections, and published national estimates of per capita excess health-care costs of obesity/overweight. The objective was to illustrate potential burden of obesity prevalence and health-care costs of obesity and overweight in the United States that would occur if current trends continue. Overweight and obesity prevalence have increased steadily among all US population groups, but with notable differences between groups in annual increase rates. The increase (percentage points) in obesity and overweight in adults was faster than in children (0.77 vs. 0.46-0.49), and in women than in men (0.91 vs. 0.65). If these trends continue, by 2030, 86.3% adults will be overweight or obese; and 51.1%, obese. Black women (96.9%) and Mexican-American men (91.1%) would be the most affected. By 2048, all American adults would become overweight or obese, while black women will reach that state by 2034. In children, the prevalence of overweight (BMI >/= 95th percentile, 30%) will nearly double by 2030. Total health-care costs attributable to obesity/overweight would double every decade to 860.7-956.9 billion US dollars by 2030, accounting for 16-18% of total US health-care costs. We continue to move away from the Healthy People 2010 objectives. Timely, dramatic, and effective development and implementation of corrective programs/policies are needed to avoid the otherwise inevitable health and societal consequences implied by our projections .