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2: Regulation of blood glucose levels by insulin and glucagon. When blood glucose tends When blood glucose tends to increase, such as is the case in the postprandial phase, insulin is released from pancreatic β-βcells, whereas in the fasting state, when glucose levels tend to be low, glucagon is released from pancreatic �-cells. Both islet hormones try to normalize blood glucose levels. Insulin's action �-cells. Both islet hormones try to normalize blood glucose levels. Insulin's action-cells. Both islet hormones try to normalize blood glucose levels. Insulin's action cells. Both islet hormones try to normalize blood glucose levels. Insulin's action lowers blood glucose by stimulating glucose uptake by tissues, utilization and storage of glucose as glycogen in the liver and muscle. The opposing actions of glucagon aim to increase plasma glucose by stimulating glycogen breakdown into glucose and release into the bloodstream.
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Cardiac patients often are obese and have hypertension, but in most studies these conditions are investigated separately. Here, we aimed at 1) elucidating the interaction of metabolic and mechanophysical stress in the development of cardiac dysfunction in mice and 2) preventing this interaction by ablation of the fatty acid transporter CD36. Male w...
Citations
... Compromised fatty acid oxidation capacity represented the major pathological change in diseased mice. While a shift from fatty acid oxidation to more oxygen-efficient glucose oxidation has been proposed to be beneficial during cardiac stress [53], inhibition of fatty acid oxidation was found to exacerbate cardiac hypertrophy caused by pressure overload [54,55], suggesting that maintaining fatty acid oxidation capacity exerts cardioprotective effects under stress conditions [56]. Thus, based on our study, it would be interesting to study if boosting cardiac fatty acid oxidation in our and other models of HCM will prevent or rather aggravate disease development due to increased oxygen demand. ...
... Exacerbation of cardiac inflammation and the associated elevation of inflammatory genes were the hallmarks of LCD-A-fed heart tissue, but no possible upstream regulators of these changes were discovered even with RNA-seq analysis. Well-used high-fat diets often consist of animal fats such as lard, which are similar to LCD-A and are associated with poorer cardiac outcomes during stress or aging [45][46][47] . Third, we could not measure the FAO or glucose oxidation rate, which remains to be clarified in future research. ...
Cardiovascular disease (CVD) is a global health burden in the world. Although low-carbohydrate diets (LCDs) have beneficial effects on CVD risk, their preventive effects remain elusive. We investigated whether LCDs ameliorate heart failure (HF) using a murine model of pressure overload. LCD with plant-derived fat (LCD-P) ameliorated HF progression, whereas LCD with animal-derived fat (LCD-A) aggravated inflammation and cardiac dysfunction. In the hearts of LCD-P-fed mice but not LCD-A, fatty acid oxidation-related genes were highly expressed, and peroxisome proliferator-activated receptor α (PPARα), which regulates lipid metabolism and inflammation, was activated. Loss- and gain-of-function experiments indicated the critical roles of PPARα in preventing HF progression. Stearic acid, which was more abundant in the serum and heart of LCD-P-fed mice, activated PPARα in cultured cardiomyocytes. We highlight the importance of fat sources substituted for reduced carbohydrates in LCDs and suggest that the LCD-P-stearic acid-PPARα pathway as a therapeutic target for HF.
... When the fatty acid concentration in the circulation rises, such as upon increased lipid consumption, the rate of fatty acid uptake increases, as governed by an increased transmembrane gradient of fatty acids and enabled by the facilitatory action of CD36. In line with this, cardiomyocytes pretreated with CD36-blocking antibodies [69] as well as hearts from CD36 knockout mice are protected from lipid overload in vitro and in vivo, respectively [70,71]. Subsequently, increased fatty acid flux through CD36 is followed by increased CD36 translocation from endosomes to the cell surface, thereby further increasing fatty acid uptake. ...
... However, whereas CD36 permanently translocates to the sarcolemma, GLUT4 remains intracellularly. It has been suggested that GLUT4 translocates from the endosomes to a non-endosomal intracellular compartment [71]. ...
The heart is a metabolically flexible omnivore that can utilize a variety of substrates for energy provision. To fulfill cardiac energy requirements, the healthy adult heart mainly uses long-chain fatty acids and glucose in a balanced manner, but when exposed to physiological or pathological stimuli, it can switch its substrate preference to alternative substrates such as amino acids (AAs) and ketone bodies. Using the failing heart as an example, upon stress, the fatty acid/glucose substrate balance is upset, resulting in an over-reliance on either fatty acids or glucose. A chronic fuel shift towards a single type of substrate is linked with cardiac dysfunction. Re-balancing myo-cardial substrate preference is suggested as an effective strategy to rescue the failing heart. In the last decade, we revealed that vacuolar-type H +-ATPase (v-ATPase) functions as a key regulator of myocardial substrate preference and, therefore, as a novel potential treatment approach for the failing heart. Fatty acids, glucose, and AAs selectively influence the assembly state of v-ATPase resulting in modulation of its proton-pumping activity. In this review, we summarize these novel insights on v-ATPase as an integrator of nutritional information. We also describe its exploitation as a therapeutic target with focus on supplementation of AA as a nutraceutical approach to fight lipid-induced insulin resistance and contractile dysfunction of the heart.
... The heart then relies almost completely on fatty acids for metabolic energy provision, cannot take up sufficient amounts of glucose, and develops contractile dysfunction [43 & ]. The pivotal early role of CD36 in this cascade of events is evidenced by the observations that genetic ablation of CD36 [44,45] or blocking its activity by specific inhibitors (e.g., sulfo-N-succinimidyl-oleate) [46][47][48] or antibodies [49] fully prevent the loss of contractile function of cardiomyocytes. ...
Purpose of review:
Transmembrane glycoprotein cluster of differentiation 36 (CD36) is a scavenger receptor class B protein (SR-B2) that serves various functions in lipid metabolism and signaling, in particular facilitating the cellular uptake of long-chain fatty acids. Recent studies have disclosed CD36 to play a prominent regulatory role in cellular fatty acid metabolism in both health and disease.
Recent findings:
The rate of cellular fatty acid uptake is short-term (i.e., minutes) regulated by the subcellular recycling of CD36 between endosomes and the plasma membrane. This recycling is governed by the activity of vacuolar-type H+-ATPase (v-ATPase) in the endosomal membrane via assembly and disassembly of two subcomplexes. The latter process is being influenced by metabolic substrates including fatty acids, glucose and specific amino acids, together resulting in a dynamic interplay to modify cellular substrate preference and uptake rates. Moreover, in cases of metabolic disease v-ATPase activity was found to be affected while interventions aimed at normalizing v-ATPase functioning had therapeutic potential.
Summary:
The emerging central role of CD36 in cellular lipid homeostasis and recently obtained molecular insight in the interplay among metabolic substrates indicate the applicability of CD36 as target for metabolic modulation therapy in disease. Experimental studies already have shown the feasibility of this approach.
... In support of this notion, strategies that reduce fatty acid uptake or promote fatty acid storage are accompanied by cardiac functional improvements in models of obesity or cardiac PPAR (peroxisome proliferator-activated receptor) activation. 4,6,38 In contrast, blocking the increase of myocardial FAO exacerbates cardiac damage in obese mice. 11 Our current observations suggest that directing more fatty acid toward oxidation in mitochondria represents another effective way to protect the heart from toxic lipids during the development of obesity. ...
Background: Increased fatty acid oxidation (FAO) has long been considered a culprit in the development of obesity/diabetes induced cardiomyopathy. However, enhancing cardiac FAO by removing the inhibitory mechanism of long-chain fatty acids transport into mitochondria via deletion of acetyl-CoA carboxylase 2 (ACC2) does not cause cardiomyopathy in non-obese mice, suggesting that high FAO is distinct from cardiac lipotoxicity. We hypothesize that cardiac pathology associated obesity is attributable to the imbalance of fatty acid supply and oxidation. Thus, we here seek to determine whether further increasing FAO by inducing ACC2 deletion prevents obesity induced cardiomyopathy, and if so, to elucidate the underlying mechanisms.
Methods: We induced high FAO in adult mouse hearts by cardiac-specific deletion of ACC2 using a tamoxifen inducible model (ACC2 iKO). Control (Con) and ACC2 iKO mice were subjected to high fat diet (HFD) feeding for 24 weeks to induce obesity. Cardiac function, mitochondria function and mitophagy activity were examined.
Results: Despite both Con and ACC2 iKO mice exhibiting similar obese phenotype, increasing FAO oxidation by deletion of ACC2 prevented HFD induced cardiac dysfunction, pathological remodeling as well as mitochondria dysfunction. Similarly, increasing FAO by knock down of ACC2 prevented palmitate induced mitochondria dysfunction and cardiomyocyte death in vitro. Furthermore, HFD suppressed mitophagy activity and caused damaged mitochondria to accumulate in the heart, which was partially attenuated in ACC2 iKO heart. Mechanistically, ACC2 iKO prevented HFD induced downregulation of parkin. During stimulation for mitophagy, mitochondria localized parkin was severely reduced in Con HFD-fed mouse heart, which was partially restored in ACC2 iKO HFD-fed mice.
Conclusions: These data show that increasing cardiac FAO alone does not cause cardiac dysfunction but protect against cardiomyopathy in chronically obese mice. The beneficial effect of enhancing cardiac FAO in HFD induced obesity is mediated, in part, by maintenance of mitochondria function through regulating parkin mediated mitophagy. Our findings also suggest that targeting the parkin dependent mitophagy pathway could be an effective strategy against the development of obesity induced cardiomyopathy.
... Доказанным в ряде работ [3,4,5] считается процесс снижения синтеза оксида азота (NO) в эндотелиальных клетках и аденозинтрифосфорной кислоты (АТФ) в миокарде вследствие повышения уровней АТ II и альдостерона и развития инсулинорезистентности (ИР) на фоне ожирения [6,7,8,9,10]. ...
Objectives - to study the indicators of humoral regulation of circulatory system in obese patients as the predictors of CHF development. Materials and methods. Two groups of 40 patients were formed: the first group consisted of patients with I or II grades obesity with BMI of up to 40 kg/m2, the second group included patients with grade III obesity with BMI of over 40 kg/m2. None of the selected patients had a history of cardiovascular events. The concentration value of renin-angiotensin-aldosterone system components and level of N-terminal pro B-type natriuretic peptide (NT-pro-BNP) was determined. Results. Aldosterone level in grade I-II obese patients was close to normal upper border: 58.9 [54.9; 73.8] pg/ml (normal range is 10-60 pg/ml), while in patients with grade III obesity it was 79.5 [64.5; 90.1], which is 25.9% higher than in patients of the first group and 24.5% higher above the normal level (p < 0.05). These two groups was significantly different not only in average plasma aldosterone level, but in absolute number of patients with hyperaldosteronism, whose number accounted for 46.2% in grades I or II obese patients and 85.7% among patients with grade III obesity. Plasma renin level and angiotensin II levels in both groups was within the normal range. NT-proBNP level in the first group was 23.7 [10.6; 23.6] pg/ml, in the second group - 138.0 [121.5; 145.9] pg/ml, which is 5.8 times higher (p = 0.001). In both groups of patients, the correlation analysis showed that aldosterone and NT-proBNP levels are closely related (r = 0.74, p < 0.05). Conclusion. This study suggests that aldosterone level can be used as a predictor of HF.
... The pivotal early role of CD36 in this cascade of events suggests that manipulation of the sarcolemmal presence or activity of CD36 should prevent and/or regress high fat diet-induced toxic lipid accumulation and contractile dysfunction. Indeed, CD36null mice are protected against high fat diet-induced loss of cardiac function 30,31 . In addition, cardiac-specific overexpression of nuclear receptor PPARα in mice resulting in enhanced cardiac fatty acid utilization and lipotoxic cardiomyopathy could be rescued by deletion of CD36 32 . ...
... An increased utilization of glucose at the expense of fatty acids is seen during pressure overload-induced cardiac hypertrophy and is accompanied by an increased presence of GLUT4 at the sarcolemma 34 . Subjecting mice with transaortic constriction-induced cardiac hypertrophy 30 or mice with genetically induced cardiac hypertrophy 35 to a dietary intervention with a high fat-containing diet, in each case elicited normalization of glucose utilization (due to increased fatty acid utilization) together with the recuperation of contractile function. In both examples, it can be inferred that GLUT4 was redistributed leading to a net relocation towards intracellular stores. ...
... In the past decade the latter have been disclosed in much detail, and found to comprise membrane proteinmediated substrate uptake involving CD36 for fatty acids and GLUT4 for glucose. Studies in experimental animal models and in pluripotent stem cell-derived human cardiomyocytes have provided the first indication that applying CD36 and/or GLUT4 as target for metabolic modulation approaches is an effective strategy to re-balance myocardial substrate preference[22,25,26]. Now that the pivotal roles of CD36 and GLUT4 have been confirmed in patient studies[11,18,27],manipulatingtheir sarcolemmal presence should be explored as treatment target for cardiac diseases also in the human setting. ...
... These in vitro findings are in line with published reports on mice in vivo, as CD36-null mice were found to be protected against high-fat dietinduced loss of cardiac function. 28,29 Together, these data indicate that lipid overload-induced increased translocation of CD36 to the sarcolemma is an early event prior to the development of insulin resistance and contractile dysfunction (Fig. 4). 7 Of note, the pivotal early role of CD36 translocation in this series of events induced by lipid oversupply to the heart was very recently confirmed to occur by another group of investigators. ...
The heart faces the challenge of adjusting the rate of fatty acid uptake to match myocardial demand for energy provision at any given moment, avoiding both too low uptake rates, which could elicit an energy deficit, and too high uptake rates, which pose the risk of excess lipid accumulation and lipotoxicity. The transmembrane glycoprotein cluster of differentiation 36 (CD36), a scavenger receptor (B2), serves many functions in lipid metabolism and signaling. In the heart, CD36 is the main sarcolemmal lipid transporter involved in the rate-limiting kinetic step in cardiac lipid utilization. The cellular fatty acid uptake rate is determined by the presence of CD36 at the cell surface, which is regulated by subcellular vesicular recycling from endosomes to the sarcolemma. CD36 has been implicated in dysregulated fatty acid and lipid metabolism in pathophysiological conditions, particularly high-fat diet-induced insulin resistance and diabetic cardiomyopathy. Thus, in conditions of chronic lipid overload, high levels of CD36 are moved to the sarcolemma, setting the heart on a route towards increased lipid uptake, excessive lipid accumulation, insulin resistance, and eventually contractile dysfunction. Insight into the subcellular trafficking machinery of CD36 will provide novel targets to treat the lipid-overloaded heart. A screen for CD36-dedicated trafficking proteins found that vacuolar-type H+-ATPase and specific vesicle-associated membrane proteins, among others, were uniquely involved in CD36 recycling. Preliminary data suggest that these proteins may offer clues on how to manipulate myocardial lipid uptake, and thus could be promising targets for metabolic intervention therapy to treat the failing heart.
... The subsequent progression from compensated cardiac hypertrophy to heart failure, which is characterized by a further reliance on glucose, is accelerated when cardiac fatty acid utilization is severely hampered by ablation of the sarcolemmal fatty acid transporter CD36 [27]. Similarly, subjecting CD36 null mice (in which the fuel balance already has been shifted towards increased glucose utilization) to mechanical stress (transverse aortic constriction) elicits a marked further impairment of contractile function [28]. ...
... Several studies have documented that interventions correcting aberrations of the fatty acid-glucose fuel balance have a beneficial effect on cardiac contractile performance. When mice with a pressure overload-induced cardiac hypertrophy and an associated shifted substrate balance towards increased glucose utilization were subjected to a dietary intervention with high-fat, both substrate balance and contractile function normalized [28]. Similarly, mice with a cardiac specific overexpression of protein kinase-D1, which leads to increased utilization of glucose and cardiac hypertrophy, also could be rescued by feeding a high-fat diet, upon which the substrate balance and contractile function each normalized [29]. ...
Fatty acids and glucose are the main substrates for myocardial energy provision. Under physiologic conditions, there is a distinct and finely tuned balance between the utilization of these substrates. Using the non-ischemic heart as an example, we discuss that upon stress this substrate balance is upset resulting in an over-reliance on either fatty acids or glucose, and that chronic fuel shifts towards a single type of substrate appear to be linked with cardiac dysfunction. These observations suggest that interventions aimed at re-balancing a tilted substrate preference towards an appropriate mix of substrates may result in restoration of cardiac contractile performance. Examples of manipulating cellular substrate uptake as a means to re-balance fuel supply, being associated with mended cardiac function underscore this concept. We also address the molecular mechanisms underlying the apparent need for a fatty acid-glucose fuel balance. We propose that re-balancing cellular fuel supply, in particular with respect to fatty acids and glucose, may be an effective strategy to treat the failing heart.
