Fig 8 - uploaded by Yea-Hyun Leem
Content may be subject to copyright.
Comparison of mRNA expression in gastrocnemius and soleus muscle between Angptl4 wild-type (WT) and knockout (KO) mice. The mRNA expression of Mn-SOD and Cu/Zn-SOD (A, C) and Tfam, NRF1, and NRF2 (B, D) in gastrocnemius muscle (A, B) and soleus (C, D). **P 0.01 vs. WT mice. Angptl4, angiopoietin-like protein 4; Cu/Zn-SOD, copper/zinc superoxide dismutase; Mn-SOD, manganese superoxide dismutase; NRF, nuclear respiratory factor; Tfam, transcription factor A.
Source publication
Angiopoietin-like protein 4 (Angptl4)/fasting-induced adipose factor (Fiaf) expression levels are increased by exercise in skeletal muscle. We have previously shown that Angptl4 regulates food intake and energy expenditure via modulation of hypothalamic AMP-activated protein kinase (AMPK) activity. AMPK is an important signaling molecule that integ...
Contexts in source publication
Context 1
... biogenesis are important for exercise endurance (28), we examined the expression of genes such as Mn-SOD, Cu/Zn-SOD, Tfam, NRF1, and NRF2 in the soleus and gastrocnemius of wild-type and knockout mice. Notably, Mn-SOD expression was significantly higher in soleus of Angptl4 knockout mice, and Cu/Zn-SOD expression also tended to be higher (Fig. 8A). Mitochondrial transcription factor Tfam tended to decrease in the soleus of Angptl4 knockout mice (Fig. 8B), although this alteration was not observed in the gastrocnemius of Angptl4 knockout mice (Fig. 8, C and ...
Context 2
... Cu/Zn-SOD, Tfam, NRF1, and NRF2 in the soleus and gastrocnemius of wild-type and knockout mice. Notably, Mn-SOD expression was significantly higher in soleus of Angptl4 knockout mice, and Cu/Zn-SOD expression also tended to be higher (Fig. 8A). Mitochondrial transcription factor Tfam tended to decrease in the soleus of Angptl4 knockout mice (Fig. 8B), although this alteration was not observed in the gastrocnemius of Angptl4 knockout mice (Fig. 8, C and ...
Context 3
... Notably, Mn-SOD expression was significantly higher in soleus of Angptl4 knockout mice, and Cu/Zn-SOD expression also tended to be higher (Fig. 8A). Mitochondrial transcription factor Tfam tended to decrease in the soleus of Angptl4 knockout mice (Fig. 8B), although this alteration was not observed in the gastrocnemius of Angptl4 knockout mice (Fig. 8, C and ...
Context 4
... biogenesis are important for exercise endurance (28), we examined the expression of genes such as Mn-SOD, Cu/Zn-SOD, Tfam, NRF1, and NRF2 in the soleus and gastrocnemius of wild-type and knockout mice. Notably, Mn-SOD expression was significantly higher in soleus of Angptl4 knockout mice, and Cu/Zn-SOD expression also tended to be higher (Fig. 8A). Mitochondrial transcription factor Tfam tended to decrease in the soleus of Angptl4 knockout mice (Fig. 8B), although this alteration was not observed in the gastrocnemius of Angptl4 knockout mice (Fig. 8, C and ...
Context 5
... Cu/Zn-SOD, Tfam, NRF1, and NRF2 in the soleus and gastrocnemius of wild-type and knockout mice. Notably, Mn-SOD expression was significantly higher in soleus of Angptl4 knockout mice, and Cu/Zn-SOD expression also tended to be higher (Fig. 8A). Mitochondrial transcription factor Tfam tended to decrease in the soleus of Angptl4 knockout mice (Fig. 8B), although this alteration was not observed in the gastrocnemius of Angptl4 knockout mice (Fig. 8, C and ...
Context 6
... Notably, Mn-SOD expression was significantly higher in soleus of Angptl4 knockout mice, and Cu/Zn-SOD expression also tended to be higher (Fig. 8A). Mitochondrial transcription factor Tfam tended to decrease in the soleus of Angptl4 knockout mice (Fig. 8B), although this alteration was not observed in the gastrocnemius of Angptl4 knockout mice (Fig. 8, C and ...
Citations
... Malonyl-coa is the major precursor for fatty acid synthesis and plays a pivotal role in controlling mitochondrial fatty acid β-oxidation [21]. aNGPtl4 treatment increases the phosphorylation of aMPK and acaca, as well as the mitochondrial maximum respiratory capacity [22]. transcriptome analysis and quantitative reverse transcription polymerase chain reaction have revealed that aNGPtl4 and acaca play a crucial role in response to hypobaric hypoxia [23]. ...
... Dysregulation of aNGPtl4 in podocytes under hyperlipidemia may be enacted through the aMPK/ acaca signalling pathway [39], which plays a crucial role in exercise-induced aMPK/acaca activation in skeletal muscle [22]. Both in vivo and in vitro studies have shown that the role of aNGPtl4 may be activated through the acaca signaling pathway, consistent with our PPi results. ...
Background
Angiopoietin-like protein 4 (ANGPTL4) is recognized as a crucial regulator in lipid metabolism. Acetyl-CoA carboxylases (ACACAs) play a role in the β-oxidation of fatty acids. Yet, the functions of ANGPTL4 and ACACA in dyslipidemia of obstructive sleep apnea (OSA) remain unclear.
Methods
This study included 125 male OSA subjects from the Shanghai Sleep Health Study (SSHS) who were matched for age, body mass index (BMI), and lipid profile. Serum ANGPTL4 levels were measured via ELISA. The ANGPTL4 T266M variants of 4455 subjects along with their anthropometric, fasting biochemical, and standard polysomnographic parameters were collected. Linear regression was used to analyze the associations between quantitative traits and ANGPTL4 T266M. Molecular docking and molecular dynamic simulation were employed to compare the effects of the wild-type ANGPTL4 and its T266M mutation on ACACA.
Results
Serum ANGPTL4 levels significantly decreased with increasing OSA severity (non-OSA: 59.6 ± 17.4 ng/mL, mild OSA: 50.0 ± 17.5 ng/mL, moderate OSA: 46.3 ± 15.5 ng/mL, severe OSA: 19.9 ± 14.3 ng/mL, respectively, p = 6.02 × 10⁻¹⁶). No associations were found between T266M and clinical characteristics. Molecular docking indicated that mutant ANGTPL4 T266M had stronger binding affinity for the ACACA protein, compared with wild-type ANGPTL4. In terms of protein secondary structure, mutant ANGTPL4 T266M demonstrated greater stability than wild-type ANGPTL4.
Conclusions
Serum ANGTPL4 levels were significantly decreased in OSA patients, particularly among individuals with severe OSA. Although functional ANGTPL4 T266M variants were not associated with lipid levels in OSA, ANGTPL4 T266M could enhance binding affinity for the ACACA protein, potentially regulating lipid metabolism.
... Recently, Chang et al. suggested ANGPTL4 as a regulator of exercise-induced AMPK phosphorylation through a possible negative feedback mechanism (Chang et al., 2018). Treatment with 45, 450, and 4500 ng/ml ANGPTL4 was found to increase AMPK phosphorylation in C2C12 myotubes, with 45 ng/ml being the most effective. ...
... Taken together, the literature shows a bi-directional relationship between ANGPTL4 and AMPK, where ANGPTL4 increases AMPK signalling which in turn downregulates it. Some have therefore suggested the two are involved in a negative feedback mechanism (Chang et al., 2018). ...
Myokines are peptides and proteins secreted by skeletal muscle cells, into the interstitium, or in the blood. Their regulation may be dependent or independent of muscle contraction to induce a variety of metabolic effects. Numerous myokines have been implicated in influencing energy metabolism via AMP-activated protein kinase (AMPK) signalling. As AMPK is centrally involved in glucose and lipid metabolism, it is important to understand how myokines influence its signalling, and vice versa. Such insight will better elucidate the mechanism of metabolic regulation during exercise and at rest. This review encompasses the latest research conducted on the relationship between AMPK signalling and myokines within skeletal muscles via autocrine or paracrine signalling.
... Metabolic stresses, such as acute bouts of exercise, fasting and caloric restriction, induce the expression of ANGPTL4 in human skeletal muscle (Catoire et al., 2014), likely by increasing plasma free-fatty acid levels and activating the peroxisome proliferator-activated receptor-δ (PPAR-δ) (Staiger et al., 2009). ANGPTL4 stimulates lipolysis in WAT, determining a shift from fat storage to fat release, and triggers AMP-activated protein kinase (AMPK) in skeletal muscle, thereby mediating an increase in its mitochondrial oxidative capacity and ATP production (Norheim et al., 2014;Chang et al., 2018;Li et al., 2020). It should be noted that besides skeletal muscle, adipose tissue and the liver express higher levels of ANGPTL4 following exercise, likely contributing even more than skeletal muscle to ANGPTL4 exercise-mediated effects (Norheim et al., 2014). ...
Skeletal muscle plays a major role in controlling body mass and metabolism: it is the most abundant tissue of the body and a major source of humoral factors; in addition, it is primarily responsible for glucose uptake and storage, as well as for protein metabolism. Muscle acts as a metabolic hub, in a crosstalk with other organs and tissues, such as the liver, the brain, and fat tissue. Cytokines, adipokines, and myokines are pivotal mediators of such crosstalk. Many of these circulating factors modulate histone deacetylase (HDAC) expression and/or activity. HDACs form a numerous family of enzymes, divided into four classes based on their homology to their orthologs in yeast. Eleven family members are considered classic HDACs, with a highly conserved deacetylase domain, and fall into Classes I, II, and IV, while class III members are named Sirtuins and are structurally and mechanistically distinct from the members of the other classes. HDACs are key regulators of skeletal muscle metabolism, both in physiological conditions and following metabolic stress, participating in the highly dynamic adaptative responses of the muscle to external stimuli. In turn, HDAC expression and activity are closely regulated by the metabolic demands of the skeletal muscle. For instance, NAD+ levels link Class III (Sirtuin) enzymatic activity to the energy status of the cell, and starvation or exercise affect Class II HDAC stability and intracellular localization. SUMOylation or phosphorylation of Class II HDACs are modulated by circulating factors, thus establishing a bidirectional link between HDAC activity and endocrine, paracrine, and autocrine factors. Indeed, besides being targets of adipo-myokines, HDACs affect the synthesis of myokines by skeletal muscle, altering the composition of the humoral milieu and ultimately contributing to the muscle functioning as an endocrine organ. In this review, we discuss recent findings on the interplay between HDACs and circulating factors, in relation to skeletal muscle metabolism and its adaptative response to energy demand. We believe that enhancing knowledge on the specific functions of HDACs may have clinical implications leading to the use of improved HDAC inhibitors for the treatment of metabolic syndromes or aging.
... For example, ANGPTL4 treatment upregulated the AMPK signaling and improved the mitochondrial respiratory capacity in skeletal muscle. This can explain how ANGPTL4 may be capable of increasing exercise tolerance time via the AMPKmediated signaling pathway [109]. However, to the best our knowledge, previous studies are lacking in terms of identifying a marker of mitochondrial function. ...
Exercise has health benefits and prevents a range of chronic diseases caused by physiological and biological changes in the whole body. Generally, the metabolic regulation of skeletal muscle through exercise is known to have a protective effect on the pathogenesis of metabolic syndrome, non-alcoholic fatty liver disease (NAFLD), type 2 diabetes (T2D), and cardiovascular disease (CVD). Besides this, the importance of the liver as an endocrine organ is a hot research topic. Hepatocytes also secrete many hepatokines in response to nutritional conditions and/or physical activity. In particular, certain hepatokines play a major role in the regulation of whole-body metabolic homeostasis. In this review, we summarize the recent research findings on the exercise-mediated regulation of hepatokines, including fibroblast growth factor 21, fetuin-A, angiopoietin-like protein 4, and follistatin. These hepatokines serve as molecular transducers of the metabolic benefits of physical activity in chronic metabolic diseases, including NAFLD, T2D, and CVDs, in various tissues.
... Immediately after an acute bout of endurance and strength exercise, both serum and skeletal muscle ANGPTL4 mRNA increase in healthy, sedentary middle-aged men [3]. Similar findings are observed in animal models where 50 min of running significantly increases ANGPTL4 protein and mRNA expression levels in gastrocnemius and soleus muscles in mice [15]. ANGPTL4 is released mainly from the liver in response to exercise in animals [5]. ...
... ANGPLT4 may be an exercise responsive myokine. An acute bout of exercise in mice results in the upregulation of skeletal muscle ANGPTL4 [15]. Norheim et al. reported that, immediately after and 2 h post exercise at baseline and after the completion of a 12-week training period, serum ANGPTL4 level and skeletal muscle ANGPTL4 mRNA increased during acute exercise and remained higher after 2 h [3]. ...
... Further, oil Red O staining showed that lipid droplets accumulated diffusely in the liver of Adv-ANGPTL4-treated mice, suggesting that ANGPTL4 overexpression induces a fatty liver [12]. ANGPTL4 treatment activates AMP-activated protein (AMPK) signaling and mitochondrial oxidative capacity in skeletal muscle [15] and mice deficient in ANGPTL4 have a lower exercise endurance capacity [15]. This might suggest that muscle ANGPTL4 would be directly related to VO2max, in contrast to our findings. ...
Angiopoietin-like protein 4 (ANGPTL4) is an adipokine that plays an important role in energy homoeostasis and lipid and lipoprotein metabolism. This study was designed to determine the effect of an exercise plus weight loss intervention on ANGPTL4 expression and its relationship with metabolic health. Thirty-five obese sedentary men (n = 18) and postmenopausal women (n = 17), (X ± SEM, age: 61 ± 1 years, BMI: 31.3 ± 0.7 kg/m2, VO2max: 21.7 ± 0.9 L/kg/min) completed a 6 month program of 3×/week aerobic exercise and 1×/week dietary instruction to induce weight loss (AEX + WL). Participants underwent vastus lateralis muscle biopsies, a hyperinsulinemic–euglycemic clamp, oral glucose tolerance tests and body composition testing. Basal skeletal muscle ANGPTL4 mRNA was lower in men than women (p < 0.01). Peroxisome proliferator-activated receptor (PPAR) alpha (PPARα) mRNA expression was higher in men than women (p < 0.05). There were no significance changes in serum or skeletal muscle ANGPTL4 (basal or insulin-stimulated) or muscle PPARα mRNA expression after AEX + WL. Muscle mRNA ANGPTL4 is correlated with serum ANGPTL4 (r = 0.41, p < 0.05), body fat (r = 0.64, p < 0.0001), and glucose utilization (r = 0.38, p < 0.05). AEX + WL does not change basal or insulin-stimulated skeletal muscle ANGPTL4 mRNA expression, suggesting other factors contribute to improved insulin sensitivity after the loss of body fat and improved fitness.
... Generating mice that are deficient both in liver and adipose ANGPTL4 might allow for a greater interrogation of ANGPTL4's role in obesity, metabolic syndrome, and insulin resistance while circumventing the HFDinduced intestinal phenotype observed in whole body Angptl4 -/-mice. ANGPTL4 is expressed, although at lower levels, in skeletal muscle and heart (22) and could have important actions during exercise (23) or situations of lipotoxicity (24). ANGPTL4 expressed in the intestine has also been implicated in the effects of the intestinal microbiota on metabolism (17). ...
Elevated plasma triglyceride levels are associated with metabolic disease. Angiopoietin-like protein 4 (ANGPTL4) regulates plasma triglyceride levels by inhibiting lipoprotein lipase (LPL). ANGPTL4-deficient mice have decreased plasma triglyceride levels and increased adipose triglyceride uptake. ANGPTL4 is largely expressed by adipose and liver; therefore, we generated adipose- and liver-specific ANGPTL4 knockout mice. Mice lacking adipose ANGPTL4 recapitulated the triglyceride phenotypes of whole-body ANGPTL4 deficiency, whereas mice lacking liver ANGPTL4 had no triglyceride phenotypes. When fed a high fat diet (HFD) mice deficient in adipose ANGPTL4 gained more weight, had enhanced adipose LPL activity, and initially had improved glucose and insulin sensitivity. However, this improvement was largely lost after 6 months on HFD. Conversely, liver-deficient ANGPTL4 mice initially displayed no differences in glucose homeostasis, but began to manifest improved glucose tolerance after 6 months on HFD. We conclude that adipose derived ANGPTL4 is responsible for triglyceride regulation, while both adipose- and liver-derived ANGPTL4 may play a role in glucose homeostasis.
... Also, it was reported that ANGPTL-4 is expressed in a variety of tissues (guts, liver, adipose tissues and others) as well as tumors [7]. Furthermore, ANGPTL-4 is involved in vascular permeability, angiogenesis, and inflammatory signaling, and may also be involved in the progression of metastatic tumors [13]. ...
... Previous studies have demonstrated that ANGPTL-4 expression is regulated by hypoxia in both endothelial cells [13] and tumor cells [21]. The studies are controversial when considering ANGPTL-4 involvement in cancer. ...
Background:
Contradictory results are reported for the role of angiopoietin-like 4 (ANGPTL-4) in the development of cancer-cachexia and inflammation, given its importance in angiogenesis and inflammatory signaling. Our aim was to analyze the levels of ANGPTL-4 in colorectal cancer patients with a stable weight and those with cachexia in order to establish a relationship between ANGPTL-4 and the inflammatory process.
Results:
Plasma and tumor levels of ANGPTL-4 were higher in CC in comparison to other groups. A positive association was verified between plasmatic ANGPTL-4 and NFκB levels in tumor from CC. In WSC, we identified an association between the plasmatic ANGPTL-4, IL-15, and IL-10 in tumor and IL-15 in MES. Increased levels of NFκB and TNF-R1 in MES were detected in CC in comparison to WSC. Specifically in CC-group, a positive correlation was found between ANGPTL-4 levels and those of IL-1β, TNF-α, and NFκB in tumor, along with an association between ANGPTL-4 levels with IL-1β and MCP-1 levels in tumor; and ANGPTL-4 and IL-1β levels in MES.
Methods:
We studied 102 patients, who were divided into three groups: control patients (C, n=37), cancer patients with a stable weight (WSC, n=23), and cancer-cachexia patients (CC, n=42). Samples of plasma, tumor, mesenteric (MES) and subcutaneous adipose tissue were removed for the determination of ANGPTL-4 levels and other proinflammatory factors.
Conclusions:
ANGPTL-4 levels were higher in plasma and tumor of CC-group, and positively associated with pro-inflammatory and pro-tumorigenic factors. Our results suggest an opposite effect of ANGPTL-4 depending on the concentration and presence of cachexia.
... Such reduction of iron available 265 for erythropoiesis could play an important role in spaceflight anemia (27). Similarly to short-term exposure to microgravity in humans (13,16) organ (33). After 14 days of HU, we report in the present study that iron did not accumulate 280 anymore in spleen, and that liver does not yet exhibit increased iron concentrations. ...
... As shown by others, the lack of some bacteria-derived metabolites could interfere with the metabolism of energetic substrate, such as lipid and glucose metabolism (12,33), and this could play important roles in the gut-skeletal muscle axis. In this context, fasting-induced adipocyte factor (Fiaf), also known as angiopoietin like protein 4, is a key protein reducing fatty acids synthesis, adipogenesis, and lipogenesis (13). Fiaf expression is known to be negatively regulated by intestinal bacteria (2). ...
... Interestingly, GF mice exhibit higher gut Fiaf expression compared with conventionalized mice, leading among others to a reduction of triglyceride storage in peripheral tissues, including liver (2). Fiaf is a glycoprotein recognized to also promote fatty acid oxidation through AMPK activation in skeletal muscle and to attenuate muscle lipid uptake by inhibiting lipoprotein lipase activity (13,57). Here, we confirmed the data of Bäckhed and colleagues by showing that gut Fiaf gene expression is modulated by the lack/presence of gut bacteria. ...
L'hypoactivité est caractérisée par une absence de contraintes sur le système musculo-squelettique. Il est aujourd'hui reconnu que les astronautes en impesanteur ainsi que les personnes hospitalisées et/ou alitées subissent ce phénomène. Ceci ayant pour conséquence de diminuer leurs capacités fonctionnelles en altérant notamment la fonction musculaire et le transport d'oxygène. Afin d’améliorer la santé des astronautes en mission tout comme la prise en charge des patients alités, il apparait nécessaire de mieux comprendre l’étiologie des altérations physiologiques induites par l'hypoactivité. Présentant des interactions potentielles avec le muscle squelettique, le métabolisme du fer et le microbiote intestinal constituent des cibles innovantes pouvant jouer un rôle dans ces altérations. L'objectif de ce travail de thèse est d'étudier les relations existantes entre microbiote intestinal, fer et muscle squelettique en condition d'hypoactivité et d'en décrire les mécanismes sous-jacents. En s'appuyant sur des modèles animaux et humains, nos travaux mettent en évidence une redistribution du fer dans l’organisme du sujet hypoactif, provoquée en grande partie par une augmentation de la synthèse d’hepcidine. Travail princeps démontrant un impact de la modulation du microbiote intestinal sur l’endurance du muscle squelettique, nos résultats pointent le métabolisme du glucose comme un acteur potentiel, alors que des indices de dysbiose en condition d’hypoactivité sont suggérés. L’ensemble de ce travail ouvre sur de nouvelles contre-mesures et stratégies thérapeutiques innovantes dans la prise en charge de la santé des astronautes et des patients alités.
... As shown by others, the lack of some bacteria-derived metabolites could interfere with the metabolism of energetic substrate, such as lipid and glucose metabolism (12,33), and this could play important roles in the gut-skeletal muscle axis. In this context, fasting-induced adipocyte factor (Fiaf), also known as angiopoietin like protein 4, is a key protein reducing fatty acids synthesis, adipogenesis, and lipogenesis (13). Fiaf expression is known to be negatively regulated by intestinal bacteria (2). ...
... Interestingly, GF mice exhibit higher gut Fiaf expression compared with conventionalized mice, leading among others to a reduction of triglyceride storage in peripheral tissues, including liver (2). Fiaf is a glycoprotein recognized to also promote fatty acid oxidation through AMPK activation in skeletal muscle and to attenuate muscle lipid uptake by inhibiting lipoprotein lipase activity (13,57). Here, we confirmed the data of Bäckhed and colleagues by showing that gut Fiaf gene expression is modulated by the lack/presence of gut bacteria. ...
... As shown by others, the lack of some bacteria-derived metabolites could interfere with the metabolism of energetic substrate, such as lipid and glucose metabolism (12,33), and this could play important roles in the gut-skeletal muscle axis. In this context, fasting-induced adipocyte factor (Fiaf), also known as angiopoietin like protein 4, is a key protein reducing fatty acids synthesis, adipogenesis, and lipogenesis (13). Fiaf expression is known to be negatively regulated by intestinal bacteria (2). ...
... Interestingly, GF mice exhibit higher gut Fiaf expression compared with conventionalized mice, leading among others to a reduction of triglyceride storage in peripheral tissues, including liver (2). Fiaf is a glycoprotein recognized to also promote fatty acid oxidation through AMPK activation in skeletal muscle and to attenuate muscle lipid uptake by inhibiting lipoprotein lipase activity (13,57). Here, we confirmed the data of Bäckhed and colleagues by showing that gut Fiaf gene expression is modulated by the lack/presence of gut bacteria. ...
Bacteria sheltered in gut impact on the physiology and function of several distant organs such as liver, adipose tissue or brain1. A functional cross talk between gut microbiota and skeletal muscle has also been recently discussed in the literature2. However this hypothesis requires more experimental support. Here we investigated in mice whether skeletal muscle remodeling could affect gut microbiota signature and pertinent intestinal mRNA genes expression related to muscle metabolism. We showed that mice invalidated for myostatin, a lean model presenting hypertrophic fatigable muscles3,4, display a specific microbiota signature characterized notably by a decrease of Firmicutes and Proteobacteria phyla. We also highlighted in the distal intestine an over-expression of Fiaf mRNA, a fat storage inhibitor5 and this could contribute to the specific lean phenotype of myostatin KO mice. Furthermore, 4 weeks of aerobic endurance training was associated with a normalization of gut microbiota signature (and phyla abundance) of KO-myostatin mice towards the WT profile. Interestingly, we also observe a normalization of expression of some intestinal mRNA markers including Fiaf. Altogether our results suggest a cross-talk between muscle remodeling and gut microbiota. Further understanding of the underlying mechanisms could open new therapeutic strategies for muscle- related disorders.
