Acid Oxidation In Skeletal Muscle Research Articles

411 Awardee Talk: Fetal Programming and Molecular Characterization of the Skeletal Muscle Development in Ruminants

Abstract Three experiments were developed aiming to investigate the effects of maternal nutrition on the skeletal muscle development and metabolism of the offspring. The first study was designed to evaluate the protein restriction during mid-gestation on the skeletal muscle growth of beef cattle offspring. Our results revealed that maternal protein restriction at this stage of gestation caused a decreased number of muscle fibers in the offspring. The second and third studies aimed to elucidate the effects of maternal feed restriction during different stages of gestation on the transcriptome and proteome profile in the skeletal muscle of the newborn. In these experiments, pregnant goats were feed-restricted (at 50% maintenance requirements) either during the first or second half of gestation. Transcriptome analysis revealed that feed restriction at first half of gestation upregulated genes involved with the maintenance of satellite cells, and fatty acid oxidation in skeletal muscle of the newborn. On the other hand, restriction at the second half of gestation upregulated genes related with the balance of glucose metabolism, in addition to protective mechanisms against the oxidative stress in the skeletal muscle of the newborn. Through the proteomic analysis, we observed enriched biological processes (BP) and signaling pathways (SP) related with the energy-investment phase of glycolysis, in addition to the increase in the usage of glycogen and fatty acids storages in the skeletal muscle of the newborn due to feed restriction at the first half of gestation. We also observed that when feed restriction occurs at second half of gestation there is an enrichment in BP and SP associated with the energy-generation phase of glycolysis, and an enhancement in the biosynthesis of glutamine in skeletal muscle of the newborns. Overall, the results of these studies bring insights that help to develop nutritional strategies during early life development aiming to improve postnatal performance.

CB1 Ligand AM251 Induces Weight Loss and Fat Reduction in Addition to Increased Systemic Inflammation in Diet-Induced Obesity.

Diet-induced obesity (DIO) reduces fatty acid oxidation in skeletal muscle and decreases circulating levels of adiponectin. Endocannabinoid signaling is overactive in obesity, with some effects abated by antagonism of cannabinoid receptor 1 (CB1). This research aimed to determine if treatment with the global CB1 antagonist/inverse agonist, AM251, in high-fat diet (HFD) fed rats influenced adiponectin signaling in skeletal muscle and a “browning” of white adipose tissue (WAT) defined by UCP1 expression levels. Male Sprague Dawley rats consumed an HFD (21% fat) for 9 weeks before receiving daily intraperitoneal injections with vehicle or AM251 (3 mg/kg) for 6 weeks. mRNA expression of genes involved in metabolic functions were measured in skeletal muscle and adipose tissue, and blood was harvested for the measurement of hormones and cytokines. Muscle citrate synthase activity was also measured. AM251 treatment decreased fat pad weight (epididymal, peri-renal, brown), and plasma levels of leptin, glucagon, ghrelin, and GLP-1, and increased PAI-1 along with a range of pro-inflammatory and anti-inflammatory cytokines; however, AM251 did not alter plasma adiponectin levels, skeletal muscle citrate synthase activity or mRNA expression of the genes measured in muscle. AM251 treatment had no effect on white fat UCP1 expression levels. AM251 decreased fat pad mass, altered plasma hormone levels, but did not induce browning of WAT defined by UCP1 mRNA levels or alter gene expression in muscle treated acutely with adiponectin, demonstrating the complexity of the endocannabinoid system and metabolism. The CB1 ligand AM251 increased systemic inflammation suggesting limitations on its use in metabolic disorders.

Up-regulation of thioesterase superfamily member 2 in skeletal muscle promotes hepatic steatosis and insulin resistance in mice.

Thioesterase superfamily member 2 (Them2) is highly expressed in liver and oxidative tissues, where it hydrolyzes long-chain fatty acyl-CoA esters to free fatty acids and CoA. Although mice globally lacking Them2 (Them2-/- ) are protected against diet-induced obesity, hepatic steatosis (HS), and insulin resistance (IR), liver-specific Them2-/- mice remain susceptible. The aim of this study was to test whether Them2 activity in extrahepatic oxidative tissues is a primary determinant of HS and IR. Upon observing IR and up-regulation of Them2 in skeletal, but not cardiac, muscle of high-fat-diet (HFD)-fed wild-type compared to Them2-/- mice, we created mice with Them2 specifically deleted in skeletal (S-Them2-/- ) and cardiac muscle (C-Them2-/- ), as well as in adipose tissue (A-Them2-/- ). When fed an HFD, S-Them2-/- , but not C-Them2-/- or A-Them2-/- , mice exhibited reduced weight gain and improved glucose homeostasis and insulin sensitivity. Reconstitution of Them2 expression in skeletal muscle of global Them2-/- mice, using adeno-associated virus, was sufficient to restore excess weight gain. Increased rates of fatty acid oxidation in skeletal muscle of S-Them2-/- mice contributed to protection from HFD-induced HS by increasing VLDL triglyceride secretion rates in response to greater demand. Increases in insulin sensitivity were further attributable to alterations in production of skeletal muscle metabolites, including short-chain fatty acids, branched-chain amino acids, and pentose phosphate pathway intermediates, as well as in expression of myokines that modulate insulin responsiveness. These results reveal a key role for skeletal muscle Them2 in the pathogenesis of HS and IR and implicate it as a target in the management of NAFLD.

Intracellular localization of AMP deaminase and its novel role in BCAA and lipid metabolism in diabetic cardiomyopathy

Abstract Background A metabolomic study in the human heart suggested a pivotal role of amino acid (AA) metabolism in fatty acid oxidation, which is dysregulated in type 2 diabetes mellitus (T2DM) and heart failure. We previously reported that aberrant up-regulation of AMP deaminase 3 (AMPD3) impairs cardiac energetics in T2DM hearts, and AMPD3 was recently shown to be activated by fasting and to promote AA metabolism and fatty acid oxidation in skeletal muscle. A sodium glucose cotransporter 2 inhibitor (SGLT2i) has been shown to augment systemic AA metabolism, but its effect on cardiac AA metabolism remains unknown. Purpose We hypothesized that AMPD3 has a role in AA and lipid metabolism in cardiomyocytes and that the protective effect of an SGLT2i in diabetic hearts is mediated by modification of AA and lipid metabolism. Methods and results Proteomic analyses of AMPD3 immunoprecipitates in rat hearts revealed that AMPD3 interacted with the E1α and E2 components of the BCKDH complex, a rate-limiting enzyme of branched-chain AA (BCAA) catabolism. Immunoblotting using subcellular fractions revealed that BCKDH localized not only in the mitochondria matrix but also in the cytosol and endoplasmic reticulum (ER) and that AMPD3 interacted with BCKDH in the cytosol and ER. Despite comparable expression of BCKDH components and phosphorylation of E1α at Ser293, significant accumulation of BCAA was observed in T2DM rats (OLETF; 317±30 nmol/g) compared to that in control rats (LETO; 213±16 nmol/g), and the accumulation of BCAA was accompanied by up-regulation of AMPD3 in the cytosol and ER by 98% and 231%, respectively. In cardiomyocytes, disruption of BCAA catabolism by knockdown of BCKDH-E1α resulted in a 5.8-fold increase in AMPD3 at the transcriptional level and blunted lipid droplet biogenesis in response to a long-chain fatty acid challenge. Next, myocardial infarction (MI) was induced in LETO and OLETF pretreated with empagliflozin (10 mg/kg/day, 14 days) or a vehicle. Pathway analysis of cardiac metabolites revealed arginine biosynthesis and BCAA metabolism as the most significantly changed pathways with empagliflozin, with BCAA (791±187 nmol/g), glutamate, glutamine and urea being significantly increased. Empagliflozin restored myocardial ATP and survival after MI in OLETF to levels comparable to those in LETO. Electron microscopy showed a significantly higher prevalence of myocardium lipid droplets in OLETF, which was further increased by empagliflozin. Conclusions The results support the hypotheses that imbalance of extra-mitochondrial AMPD3-BCKDH interaction underlies dysregulated BCAA metabolism in T2DM hearts and that activation of cardiac AA metabolism by an SGLT2i normalizes fatty acid overload through sequestration into intracellular lipid droplets. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Boehringer Ingelheim

Tuning fatty acid oxidation in skeletal muscle with dietary fat and exercise.

Both the consumption of a diet rich in fatty acids and exercise training result in similar adaptations in several skeletal muscle proteins. These adaptations are involved in fatty acid uptake and activation within the myocyte, the mitochondrial import of fatty acids and further metabolism of fatty acids by β-oxidation. Fatty acid availability is repeatedly increased postprandially during the day, particularly during high dietary fat intake and also increases during, and after, aerobic exercise. As such, fatty acids are possible signalling candidates that regulate transcription of target genes encoding proteins involved in muscle lipid metabolism. The mechanism of signalling might be direct or indirect targeting of peroxisome proliferator-activated receptors by fatty acid ligands, by fatty acid-induced NAD+-stimulated activation of sirtuin 1 and/or fatty acid-mediated activation of AMP-activated protein kinase. Lactate might also have a role in lipid metabolic adaptations. Obesity is characterized by impairments in fatty acid oxidation capacity, and individuals with obesity show some rigidity in increasing fatty acid oxidation in response to high fat intake. However, individuals with obesity retain improvements in fatty acid oxidation capacity in response to exercise training, thereby highlighting exercise training as a potential method to improve lipid metabolic flexibility in obesity.

A better workout without PHD3

PHD3 deficiency increases fatty acid oxidation in skeletal muscle and improves endurance exercise performance.

Genistein stimulates insulin sensitivity through gut microbiota reshaping and skeletal muscle AMPK activation in obese subjects

ObjectiveObesity is associated with metabolic abnormalities, including insulin resistance and dyslipidemias. Previous studies demonstrated that genistein intake modifies the gut microbiota in mice by selectively increasing Akkermansia muciniphila, leading to...

It's well and truly time to stop stating that AMPK regulates glucose uptake and fat oxidation during exercise.

None for Perspective.

Empagliflozin restores lowered exercise endurance capacity via the activation of skeletal muscle fatty acid oxidation in a murine model of heart failure

Decreased exercise capacity, which is an independent predictor of the poor prognosis of patients with heart failure (HF), is attributed to markedly impaired skeletal muscle mitochondrial function and fatty acid oxidation. Previous studies reported that the administration of an inhibitor of sodium-glucose cotransporter 2 (SGLT2) increases ketone body production and fat utilization in type 2 diabetic mice. In this study, we investigated the effects of SGLT2 inhibitor administration on exercise endurance and skeletal muscle mitochondrial function with fatty acid oxidation in a murine model of HF after the induction of myocardial infarction (MI). Two weeks post-MI, HF mice were divided into 2 groups, i.e., with or without treatment with the SGLT2 inhibitor empagliflozin (Empa, 300 mg/kg of food). Consistent with previous studies, urinary glucose and blood beta-hydroxybutyrate levels were increased in the HF+Empa mice compared with the sham and HF mice 4 weeks after the start of Empa administration. Exercise endurance capacity was limited in the HF mice but was ameliorated in the HF+Empa mice, without any effects on cardiac function, food intake, spontaneous physical activity, skeletal muscle strength, and skeletal muscle weight. Mitochondrial oxidative phosphorylation capacity with fatty acid substrates was reduced in the skeletal muscle of HF mice, and this decrease was ameliorated in the HF+Empa mice. Our results demonstrate that SGLT2 inhibitors may be novel therapeutics against reduced exercise endurance capacity in HF, by improving mitochondrial fatty acid oxidation in skeletal muscle.

1775-P: Impact of Acetyl-CoA Carboxylase 2 Inhibition on Skeletal Muscle Diacylglycerol and Ceramide Levels and Its Potential Contribution to Improved Glucose Metabolism

Intramyocellular lipid (IMCL) accumulation in skeletal muscle is closely associated with the development of insulin resistance. In particular, bioactive lipids such as diacylglycerol (DAG) and ceramide (Cer) have great impact on muscle insulin action. We have recently demonstrated that inhibition of acetyl-CoA carboxylase 2 (ACC2), which negatively modulates mitochondrial fatty acid oxidation in skeletal muscle, reduced IMCL levels and improved glucose metabolism in rodents. To further investigate the underlying mechanism, we examined the impact of pharmacological ACC2 inhibition on bioactive lipid composition and metabolic functions in skeletal muscle of rats, using an ACC2 selective inhibitor, compound A. As compared with vehicle treatment, chronic treatment with compound A significantly reduced both DAG and Cer levels in skeletal muscle of nondiabetic rats, which were strongly correlated with IMCL levels. Compound A also reduced the acyl-CoA pool along with enhanced acylcarnitine formation in skeletal muscle, while there were no differences in other bioactive lipid levels and DAG or Cer synthetic gene expression levels. Similarly, in Zucker diabetic fatty (ZDF) rats, compound A reduced both DAG and Cer levels in skeletal muscle without suppressing the synthetic gene expression levels. Treatment with compound A led to improved hyperinsulinemia and upregulated expression of key regulators in energy metabolism, such as Glut4 and Pgc1α, in skeletal muscle. Moreover, these positive effects on glucose metabolism were strongly correlated with diacylglycerol and ceramide reductions. Collectively, these findings suggest that ACC2 inhibition leads to preferential reductions of DAG and Cer by directly decreasing acyl-CoA pool via fatty acid oxidation in skeletal muscle, and these lipid reductions are closely linked to the improvement of glucose metabolism by ACC2 inhibition. Disclosure H. Takagi: None. T. Ikehara: None. K. Hashimoto: None. A. Shimazaki: None. Y. Kashiwagi: None. Y. Nishiura: None. M. Notoya: None. H. Yukioka: None.

291-LB: Long Noncoding RNA H19 Improves Insulin Resistance in Skeletal Muscle by Regulating Heterogeneous Nuclear Ribonucleoprotein A1

Skeletal muscles play a pivotal role in glucose and lipid metabolism, and it has become a consensus that impaired lipid metabolism leads to ectopic lipid accumulation in skeletal muscles, which ultimately causes systematic insulin resistant. Previous reports have shown that down-regulation of long non-coding RNA(lncRNA) H19 in skeletal muscle impairs glucose metabolism. To better understand the impact of H19 on insulin resistance, here we focused on the relationships between H19 and fatty acid metabolism in skeletal muscle. In our research, decreased H19 expression was found in skeletal muscle of db/db mice compared with db/m mice. In vivo overexpression of H19 via injection of recombinant H19-adenovirus by tail-vein in db/db mice significantly improved glucose tolerance, lowered serum insulin, TG and skeletal muscle TG levels, which were consistent with improved skeletal muscle H&E and oil red staining contrast to vehicle-treated db/db mice, indicating that overexpression of H19 in db/db mice ameliorated ectopic lipid accumulation in skeletal muscle. As expected, similar effects were observed in vitro. Overexpression of H19 in muscle cells treated with palmitate acid reduced lipid contents,promoted mitochondrial synthesis and ATP productions,and increased the expression of fatty acid oxidation related genes and mitochondrial respiratory chain complexes.Finally, it was drawn from RNA pull-down and RIP that heterogeneous nuclear ribonucleoprotein A1(hnRNPA1)is the target gene of H19, whose function in mitochondria has not been reported yet. Furthermore, we identified PGC1a and CPT1b were among the target genes of hnRNPA1 by searching widely used bioinformatics databases and preliminary RIP validation. Based on these results, we put forth our hypothesis that lncRNA H19 could improve insulin resistance by promoting mitochondrial biosynthesis and fatty acid oxidation in skeletal muscle, through regulating hnRNPA1. Disclosure X. Lin: None. W. Gui: None. H. Li: None. Funding National Natural Science Foundation of China (81873653)

Loss of Carnitine Palmitoyltransferase‐2 in skeletal muscle results in muscle remodeling and tissue‐specific sensitivity to insulin

Dysregulated mitochondrial fatty acid oxidation in skeletal muscle occurs with overfeeding and obesity and is implicated in the development of insulin resistance. To assess the effects of eliminating mitochondrial long‐chain fatty acid oxidation on insulin sensitivity we generated mice with a muscle‐specific deficiency in Carnitine Palmitoyltransferase‐2 (Cpt2Sk−/− mice), an irreplaceable enzyme required for mitochondrial oxidation of long‐chain fatty acids.Cpt2 Sk−/− mice have lower basal glycaemia, hypo‐phosphorylation of Akt in liver and white adipose tissue with preserved Akt‐phosphorylation in muscle, and moderately increased sensitivity to glucose and insulin tolerance tests. Acute insulin stimulation increased Akt phosphorylation to similar levels in control and Cpt2 Sk−/− liver, adipose, and muscle. Thus, the induction in Akt phosphorylation from no‐insulin to insulin‐stimulated is heightened in Cpt2 Sk−/− liver and white adipose, but not in muscle.Cpt2 Sk−/− muscles are free of oxidative stress and do not accumulate lipotoxic ceramides or triacylglycerol. However, Cpt2 Sk−/− muscles, compared to controls, accumulate up to 500‐fold more long‐chain acylcarnitines. Also, Cpt2 Sk−/− muscles undergo remodeling by increasing mitochondria, fiber‐type switching, and alteration in myocyte nuclei size, number, and distribution. Taken together these data suggest that loss of muscle Cpt2 causes adaptive muscle remodeling and improves insulin sensitivity of liver and adipose, but not muscle.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

SUMO-specific protease 2 mediates leptin-induced fatty acid oxidation in skeletal muscle

Background and purposeIn addition to the central nervous system-mediated action, leptin also directly induces fatty acid oxidation in skeletal muscle. Rapid induction of FAO by leptin is mediated by the AMP-activated protein kinase (AMPK) pathway, but the mechanism of prolonged FAO by leptin was previously unknown. In an earlier study, we showed that free fatty acids increase transcription of small ubiquitin-like modifier (SUMO) specific protease 2 (SENP2) in skeletal muscle, and that SENP2 stimulates expression of FAO-associated enzymes by deSUMOylating peroxisome proliferator-activated receptors, PPARδ and PPARγ. In this study, we examine whether SENP2 is involved in prolonged stimulation of FAO by leptin. MethodsThe Effect of leptin on expression of SENP2 and on SENP2-mediated FAO was investigated by using western blotting and real time qPCR of C2C12 myotubes, and of C2C12 myotubes in which expression of specific genes was knocked down using siRNAs. Additionally, muscle-specific SENP2 knockout mice were generated to test the involvement of SENP2 in leptin-induced FAO in vivo. ResultsWe show that leptin treatment of C2C12 myotubes causes signal transducer and activator of transcription 3 (STAT3) to bind to the Senp2 promoter, inducing SENP2 expression. We also show that leptin increases the binding of PPARδ and PPARγ to PPRE sites in the promoters of two FAO-associated genes: long-chain acyl-CoA synthetase 1 (Acsl1) or carnitine palmitoyl transferase 1b (Cpt1b). When SENP2 is knocked down in myotubes, leptin-induced expression of FAO-associated enzymes and prolonged increase of FAO are suppressed, but rapid increase of FAO is unaffected. In addition, leptin-induced expression of FAO-associated enzymes was not observed in muscle tissue of SENP2 knockout mice. ConclusionsWe demonstrate that the peripheral actions of leptin on FAO are mediated by two different pathways: AMPK causes a rapid increase in FAO, and SENP2 of the STAT3 pathway causes a slow, prolonged increase in FAO.

A selective inhibitor of ceramide synthase 1 reveals a novel role in fat metabolism

Specific forms of the lipid ceramide, synthesized by the ceramide synthase enzyme family, are believed to regulate metabolic physiology. Genetic mouse models have established C16 ceramide as a driver of insulin resistance in liver and adipose tissue. C18 ceramide, synthesized by ceramide synthase 1 (CerS1), is abundant in skeletal muscle and suggested to promote insulin resistance in humans. We herein describe the first isoform-specific ceramide synthase inhibitor, P053, which inhibits CerS1 with nanomolar potency. Lipidomic profiling shows that P053 is highly selective for CerS1. Daily P053 administration to mice fed a high-fat diet (HFD) increases fatty acid oxidation in skeletal muscle and impedes increases in muscle triglycerides and adiposity, but does not protect against HFD-induced insulin resistance. Our inhibitor therefore allowed us to define a role for CerS1 as an endogenous inhibitor of mitochondrial fatty acid oxidation in muscle and regulator of whole-body adiposity.

Sarcolipin, an Uncoupler of SERCA, Protects against Lipotoxicity and Insulin Resistance

Obesity is strongly associated with insulin resistance and type 2 diabetes, and increased consumption of high-caloric diet combined with decreased physical activity have made type 2 diabetes a worldwide epidemic. Excess accumulation of lipid and fatty acid metabolites has been shown to interfere with insulin signaling in skeletal muscle. Increasing energy expenditure and mitochondrial metabolism in muscle is an attractive strategy to protect against fat-induced insulin resistance. We have previously shown that sarcolipin (SLN), an uncoupler of SERCA pump, promotes futile cycling, increases ATP utilization and heat generation thereby contributing to muscle thermogenesis. When fed with high-fat diet (HFD), Sln-KO mice developed massive obesity whereas SLN overexpression (SlnOE) mice showed resistance to obesity. In this study, we investigated if SLN based uncoupling mechanism can be targeted to enhance muscle energy expenditure and protects against fat-induced lipotoxicity and insulin resistance in skeletal muscle. Here we show that SLN overexpression increases fatty acid oxidation in skeletal muscle by reprogramming mitochondria and upregulation of enzymes involved in fatty acid transport and oxidation. Interestingly, SlnOE mice fed on high-fat diet did not show intramuscular lipid accumulation and display improved insulin sensitivity. On the other hand, Sln-KO mice show excessive lipid accumulation in muscle and defects in insulin-stimulated glucose uptake, a sign of insulin resistance. Insulin resistant phenotype of Sln-KO muscle was associated with the increased intramuscular concentration of diacylglycerols (DAG), ceramides and acylcarnitines. These results suggest that sarcolipin mediated uncoupling of SERCA is a novel therapeutic target to increase energy expenditure and prevent insulin resistance in skeletal muscle. Disclosure S.K. Maurya: None.

Adiponectin Regulation and Function.

Adipose tissue is now recognized as an important endocrine organ, capable of secreting a large number of endocrine factors which regulate a wide variety of physiological functions. Adiponectin is one such factor, secreted in large quantities primarily from adipose tissue. Adiponectin is posttranslationally modified from a 30-kDa monomeric protein into different multimers (low molecular weight or trimer, middle molecular weight or hexamer, and high molecular weight) and secreted into the circulation. Upon binding to its receptors, AdipoR1 and R2, adiponectin initiates a series of tissue-dependent signal transduction events, including phosphorylation of adenosine monophosphate (AMPK) and p38 mitogen-activated protein kinase (p38 MAPK), and increased peroxisome proliferator-activated receptor alpha (PPARα) ligand activity. These signal transduction events are regulated by adaptor protein containing a pleckstrin homology domain, phosphotyrosine binding domain, and leucine zipper motif (APPL1), which binds directly to the intracellular regions of AdipoR1 and R2. AdipoR1 and R2 also possesses inherent ceramidase activity, resulting in a decrease in intracellular ceramide, a sphingolipid that has been implicated in insulin resistance, cell death, inflammation, and atherosclerosis. Adiponectin stimulates fatty acid oxidation in skeletal muscle and inhibits glucose production in the liver, resulting in an improvement in whole-body energy homeostasis. Adiponectin is also a classic anti-inflammatory agent, reducing inflammation in various cell types through AdipoR1 and R2 signaling mechanisms. Adiponectin's anti-inflammatory and anti-apoptotic properties results in protection of the vasculature, heart, lung, and colon. In this review, we provide a comprehensive overview of the discovery, protein structure, receptors, expression, regulation, and physiological functions of adiponectin. © 2017 American Physiological Society. Compr Physiol 8:1031-1063, 2018.

Dihydrocapsiate improved age-associated impairments in mice by increasing energy expenditure.

Metabolic dysfunction is associated with aging and results in age-associated chronic diseases, including type 2 diabetes mellitus, cardiovascular disease, and stroke. Hence, there has been a focus on increasing energy expenditure in aged populations to protect them from age-associated diseases. Dihydrocapsiate (DCT) is a compound that belongs to the capsinoid family. Capsinoids are capsaicin analogs that are found in nonpungent peppers and increase whole body energy expenditure. However, their effect on energy expenditure has been reported only in young populations, and to date the effectiveness of DCT in increasing energy expenditure in aged populations has not been investigated. In this study, we investigated whether DCT supplementation in aged mice improves age-associated impairments. We obtained 5-wk-old and 1-yr-old male C57BL/6J mice and randomly assigned the aged mice to two groups, resulting in a total of three groups: 1) young mice, 2) old mice, and 3) old mice supplemented with 0.3% DCT. After 12 wk of supplementation, blood and tissue samples were collected and analyzed. DCT significantly suppressed age-associated fat accumulation, adipocyte hypertrophy, and liver steatosis. In addition, the DCT treatment dramatically suppressed age-associated increases in hepatic inflammation, immune cell infiltration, and oxidative stress. DCT exerted these suppression effects by increasing energy expenditure linked to upregulation of both the oxidative phosphorylation gene program and fatty acid oxidation in skeletal muscle. These results indicate that DCT efficiently improves age-associated impairments, including liver steatosis and inflammation, in part by increasing energy expenditure via activation of the fat oxidation pathway in skeletal muscle.

Tbc1d1 deletion suppresses obesity in leptin-deficient mice.

Variants in the gene TBC1D1 have been previously associated with obesity-related traits in several species, including humans, mice, rabbits and chicken. While in humans variants in TBC1D1 were linked to obesity, disruption of the Tbc1d1 gene reduced body weight in mice. TBC1D1 has been identified as a regulator of insulin-dependent glucose transport in skeletal muscle, however, its role in energy homeostasis in the obese state remains unclear. The impact of TBC1D1 deficiency on energy homeostasis, glucose and lipid metabolism in an established mouse model of obesity was examined. Obese leptin (ob/ob)- and Tbc1d1-double-deficient mice (D1KO-ob/ob) were generated by crossing obese B6.V.Lep(ob/ob)-mice with lean Tbc1d1-deficient mice on a C57BL/6J background. Male mice on either standard (SD) or high-fat diet (HFD) were analyzed for body weight, body composition, food intake, voluntary physical activity and energy expenditure by indirect calorimetry. Glucose and insulin tolerance as well as glucose transport and fatty acid oxidation in skeletal muscle were analyzed. In obese mice, Tbc1d1 deficiency resulted in reduced body weight on both SD and HFD. However, food intake was unchanged on SD or even increased in HFD-fed Tbc1d1-deficient mice without alterations in voluntary physical activity. Despite substantially reduced insulin-stimulated glucose transport and increased fatty acid oxidation in intact isolated skeletal muscle, obese Tbc1d1-deficient mice showed no gross changes in glycemia and glucose tolerance compared with obese controls. Indirect calorimetry revealed that obese Tbc1d1-deficient mice had a decreased respiratory quotient together with increased daily energy expenditure. In obese leptin-deficient mice, lack of TBC1D1 has no impact on feeding behavior or energy intake but results in increased energy expenditure, altered energy substrate preference with increased fatty acid oxidation and suppression of obesity. TBC1D1 may have an evolutionary conserved role in regulating energy homeostasis in vertebrates.

Adiponectin, the past two decades.

Adiponectin is an adipocyte-specific factor, first described in 1995. Over the past two decades, numerous studies have elucidated the physiological functions of adiponectin in obesity, diabetes, inflammation, atherosclerosis, and cardiovascular disease. Adiponectin, elicited through cognate receptors, suppresses glucose production in the liver and enhances fatty acid oxidation in skeletal muscle, which together contribute to a beneficial metabolic action in whole body energy homeostasis. Beyond its role in metabolism, adiponectin also protects cells from apoptosis and reduces inflammation in various cell types via receptor-dependent mechanisms. Adiponectin, as a fat-derived hormone, therefore fulfills a critical role as an important messenger to communicate between adipose tissue and other organs. A better understanding of adiponectin actions, including the pros and cons, will advance our insights into basic mechanisms of metabolism and inflammation, and potentially pave the way toward novel means of pharmacological intervention to address pathophysiological changes associated with diabetes, atherosclerosis, and cardiometabolic disease.

Adipokines in Healthy Skeletal Muscle and Metabolic Disease.

Adipose tissue not only functions as a reserve to store energy but has become of major interest as an endocrine organ, releasing signalling molecules termed adipokines which impact on other tissues, such as skeletal muscle. Adipocytes, within skeletal muscle and adipose tissue, secrete adipokines to finely maintain the balance between feed intake and energy expenditure. This book chapter focuses on the three adipokines, adiponectin, leptin and IL-6, which have potent effects on skeletal muscle during rest and exercise. Similarly, adiponectin, leptin and IL-6 enhance glucose uptake and increase fatty acid oxidation in skeletal muscle. Fatty acid oxidation is increased through activation of AMPK (adenosine monophosphate-activated protein kinase signalling) causing phosphorylation and inhibition of ACC (acetyl-coenzyme A carboxylase), decreasing availability of malonyl CoA. Leptin and adiponectin also control feed intake via AMPK signalling in the hypothalamus. Adipokines function to maintain energy homeostasis, however, when feed intake exceeds energy expenditure adipokines can become dysregulated causing lipotoxicity in skeletal muscle and metabolic disease can prevail. Cross-talk between adipocytes and skeletal muscle via correct control by adipokines is important in controlling energy homeostasis during rest and exercise and can help prevent metabolic disease.