Leptin, skeletal muscle lipids, and lipid-induced insulin resistance

2007 ◽  
Vol 293 (2) ◽  
pp. R642-R650 ◽  
Author(s):  
John J. Dube ◽  
Bankim A. Bhatt ◽  
Nikolas Dedousis ◽  
Arend Bonen ◽  
Robert M. O'Doherty
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Insulin Sensitivity ◽  
Insulin Action ◽  
Glycogen Synthase ◽  
Acid Oxidation ◽  
Fatty Acid Binding ◽  
Lipid Metabolites

Leptin-induced increases in insulin sensitivity are well established and may be related to the effects of leptin on lipid metabolism. However, the effects of leptin on the levels of lipid metabolites implicated in pathogenesis of insulin resistance and the effects of leptin on lipid-induced insulin resistance are unknown. The current study addressed in rats the effects of hyperleptinemia (HL) on insulin action and markers of skeletal muscle (SkM) lipid metabolism in the absence or presence of acute hyperlipidemia induced by an infusion of a lipid emulsion. Compared with controls (CONT), HL increased insulin sensitivity, as assessed by hyperinsulinemic-euglycemic clamp (∼15%), and increased SkM Akt (∼30%) and glycogen synthase kinase 3α (∼52%) phosphorylation. These improvements in insulin action were associated with decreased SkM triglycerides (TG; ∼61%), elevated ceramides (∼50%), and similar diacylglycerol (DAG) levels in HL compared with CONT. Acute hyperlipidemia in CONT decreased insulin sensitivity (∼25%) and increased SkM DAG (∼33%) and ceramide (∼60%) levels. However, hyperlipidemia did not induce insulin resistance or SkM DAG and ceramide accumulation in HL. SkM total fatty acid transporter CD36, plasma membrane fatty acid binding protein, acetyl Co-A carboxylase phosphorylation, and fatty acid oxidation were similar in HL compared with CONT. However, HL decreased SkM protein kinase Cθ (PKCθ), a kinase implicated in mediating the detrimental effects of lipids on insulin action. We conclude that increases in insulin sensitivity induced by HL are associated with decreased levels of SkM TG and PKCθ and increased SkM insulin signaling, but not with decreases in other lipid metabolites implicated in altering SkM insulin sensitivity (DAG and ceramide). Furthermore, insulin resistance induced by an acute lipid infusion is prevented by HL.

scholarly journals Peroxisome Proliferator-Activated Receptor (PPAR) Activation Induces Tissue-Specific Effects on Fatty Acid Uptake and Metabolism in Vivo—A Study Using the Novel PPARα/γ Agonist Tesaglitazar

Endocrinology ◽  
2004 ◽  
Vol 145 (7) ◽  
pp. 3158-3164 ◽  
Author(s):  
Bronwyn D. Hegarty ◽  
Stuart M. Furler ◽  
Nicholas D. Oakes ◽  
Edward W. Kraegen ◽  
Gregory J. Cooney
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Insulin Action ◽  
Whole Body ◽  
Peroxisome Proliferator ◽  
The Novel ◽  
High Fat

Abstract Agonists of peroxisome proliferator-activated receptors (PPARs) have emerged as important pharmacological agents for improving insulin action. A major mechanism of action of PPAR agonists is thought to involve the alteration of the tissue distribution of nonesterified fatty acid (NEFA) uptake and utilization. To test this hypothesis directly, we examined the effect of the novel PPARα/γ agonist tesaglitazar on whole-body insulin sensitivity and NEFA clearance into epididymal white adipose tissue (WAT), red gastrocnemius muscle, and liver in rats with dietary-induced insulin resistance. Wistar rats were fed a high-fat diet (59% of calories as fat) for 3 wk with or without treatment with tesaglitazar (1 μmol·kg−1·d−1, 7 d). NEFA clearance was measured using the partially metabolizable NEFA tracer, 3H-R-bromopalmitate, administered under conditions of basal or elevated NEFA availability. Tesaglitazar improved the insulin sensitivity of high-fat-fed rats, indicated by an increase in the glucose infusion rate during hyperinsulinemic-euglycemic clamp (P < 0.01). This improvement in insulin action was associated with decreased diglyceride (P < 0.05) and long chain acyl coenzyme A (P < 0.05) in skeletal muscle. NEFA clearance into WAT of high-fat-fed rats was increased 52% by tesaglitazar under basal conditions (P < 0.001). In addition the PPARα/γ agonist moderately increased hepatic and muscle NEFA utilization and reduced hepatic triglyceride accumulation (P < 0.05). This study shows that tesaglitazar is an effective insulin-sensitizing agent in a mild dietary model of insulin resistance. Furthermore, we provide the first direct in vivo evidence that an agonist of both PPARα and PPARγ increases the ability of WAT, liver, and skeletal muscle to use fatty acids in association with its beneficial effects on insulin action in this model.

Abstract T P114: Insulin Resistance in Skeletal Muscle of Chronic Stroke

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Alice S Ryan ◽  
Heidi Ortmeyer ◽  
Frederick Ivey ◽  
Charlene Hafer-Macko
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Insulin Action ◽  
Glycogen Synthase ◽  
Chronic Stroke ◽  
Whole Body ◽  
Wide Range

Risk of glucose intolerance and diabetes increases in chronic stroke. The purpose of this study was to assess insulin sensitivity and glycogen synthase (GS), a known benchmark index of insulin action in skeletal muscle, and to compare the activity of this important regulatory enzyme between paretic (P) and non-paretic (NP) skeletal muscle in chronic stroke. We measured insulin sensitivity (M) and bilateral GS fractional activity (ratio of independent to total activity), in lyophilized microdissected muscle samples obtained after an overnight fast and 2 hrs into a 3-hr 80 mU . m -2. min -1 hyperinsulinemic-euglycemic clamp in 21 stroke survivors (n=15 men, n=6 women) (age: 59±2 yrs, BMI: 31±2 kg/m 2 , X±SEM). All had hemiparetic gait after ischemic stroke (>6 months), low aerobic capacity (VO 2 peak, 19.7±1.3 ml/kg/min), and wide range of %body fat (11-48%). Leg lean mass was lower in P than NP (9.3±0.5 vs. 10.0±0.5 kg, P<0.001). Subjects had either normal glucose tolerance (n=7), impaired glucose tolerance (n=7), or diabetes (n=7) and insulin resistance (M: 38.5±2.6 umol/kgFFM/min). Insulin robustly increased GS fractional activity (basal vs. insulin) in P (2.8±0.4 vs.7.5±0.8%, P<0.00001) and NP (2.7±0.4 vs. 9.1±1.1%, P<0.00001) muscle. The %change was greater in NP than P (213±32 vs. 296±36%, P=0.04). The effect of in vivo insulin to increase GS fractional activity was associated with M in P and NP muscle (r=0.59 and r=0.49, P<0.05). In conclusion, muscle atrophy and a reduction in insulin action in paretic muscle likely contribute to whole body insulin resistance in chronic stroke.

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

2020 ◽  
Vol 8 (1) ◽  
pp. e000948 ◽  
Author(s):  
Martha Guevara-Cruz ◽  
Einar T Godinez-Salas ◽  
Monica Sanchez-Tapia ◽  
Gonzalo Torres-Villalobos ◽  
Edgar Pichardo-Ontiveros ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Insulin Sensitivity ◽  
Gut Microbiota ◽  
Fatty Acid Oxidation ◽  
Acid Oxidation ◽  
Oral Glucose ◽  
Model Assessment ◽  
Metabolic Endotoxemia

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 reduction of metabolic endotoxemia and insulin sensitivity. However, it is not known whether the consumption of genistein in humans with obesity could modify the gut microbiota reducing the metabolic endotoxemia and insulin sensitivity.Research design and methods45 participants with a Homeostatic Model Assessment (HOMA) index greater than 2.5 and body mass indices of ≥30 and≤40 kg/m2 were studied. Patients were randomly distributed to consume (1) placebo treatment or (2) genistein capsules (50 mg/day) for 2 months. Blood samples were taken to evaluate glucose concentration, lipid profile and serum insulin. Insulin resistance was determined by means of the HOMA for insulin resistance (HOMA-IR) index and by an oral glucose tolerance test. After 2 months, the same variables were assessed including a serum metabolomic analysis, gut microbiota, and a skeletal muscle biopsy was obtained to study the gene expression of fatty acid oxidation.ResultsIn the present study, we show that the consumption of genistein for 2 months reduced insulin resistance in subjects with obesity, accompanied by a modification of the gut microbiota taxonomy, particularly by an increase in the Verrucomicrobia phylum. In addition, subjects showed a reduction in metabolic endotoxemia and an increase in 5′-adenosine monophosphate-activated protein kinase phosphorylation and expression of genes involved in fatty acid oxidation in skeletal muscle. As a result, there was an increase in circulating metabolites of β-oxidation and ω-oxidation, acyl-carnitines and ketone bodies.ConclusionsChange in the gut microbiota was accompanied by an improvement in insulin resistance and an increase in skeletal muscle fatty acid oxidation. Therefore, genistein could be used as a part of dietary strategies to control the abnormalities associated with obesity, particularly insulin resistance; however, long-term studies are needed.

scholarly journals PO-193 Exercise training decreased lipid accumulation in murine skeletal muscle through Sestrin2-mediated SHIP2-JNK signaling pathway

2018 ◽  
Vol 1 (4) ◽  
Author(s):  
Tianyi Wang ◽  
Song Huang ◽  
Xiao Han ◽  
Sujuan Liu ◽  
Yanmei Niu ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Exercise Training ◽  
High Fat Diet ◽  
De Novo ◽  
Underlying Mechanism ◽  
Wild Type ◽  
High Fat

Objective Obesity is becoming increasingly prevalent and is an important contributor to the worldwide burden of diseases. It is widely accepted that exercise training is beneficial for the prevention and treatment of obesity. However, the underlying mechanism by which exercise training improving skeletal muscle lipid metabolism is still not fully described. Sestrins (Sestrin1-3) are highly conserved stress-inducible protein. Concomitant ablation of Sestrin2 and Sestrin3 has been reported to provoke hepatic mTORC1/S6K1 activation and insulin resistance even without nutritional overload and obesity, implicating that Sestrin2 and Sestrin3 have an important homeostatic function in the control of mammalian glucose and lipid metabolism. Our previous results demonstrated that physical exercise increased Sestrin2 expression in murine skeletal muscle, while the role of Sestrin2 in regulating lipid metabolism remains unknown.  SH2 domain containing inositol 5-phosphatase (SHIP2) acts as a negative regulator of the insulin signaling both in vitro and in vivo. An increased expression of SHIP2 inhibits the insulin-induced Akt activation, glucose uptake, and glycogen synthesis in 3T3-L1 adipocytes, L6 myotubes and tissues of animal models. Alterations of SHIP2 expression and/or enzymatic function appear to have a profound impact on the development of insulin resistance. However, the regulatory function of SHIP2 in lipid metabolism after exercise remains unclear. It has been reported that SHIP2 modulated lipid metabolism through regulating the activity of c-Jun N-terminal kinase (JNK) and Sterol regulatory element-binding protein-1 (SREBP-1). JNK is a subclass of mitogen-activated protein kinase (MAPK) signaling pathway in mammalian cells and plays a crucial role in metabolic changes and inflammation associated with a high-fat diet. Inhibition of JNK reduces lipid deposition and proteins level of fatty acid de novo synthesis in liver cells. It has been reported that Sestrin2 regulated the phosphorylation of JNK, however the underlying mechanism remains unclear. SREBP-1 is important in regulating cholesterol biosynthesis and uptake and fatty acid biosynthesis, and SREBP-1 expression produces two different isoforms, SREBP-1a and SREBP-1c. SREBP-1c is responsible for regulating the genes required for de novo lipogenesis and its expression is regulated by insulin. SREBP-1a regulates genes related to lipid and cholesterol production and its activity is regulated by sterol levels in the cell. Altogether, the purpose of this study was to explore the effect and underlying mechanism of Sestrin2 on lipid accumulation after exercise training. Methods Male wild type and SESN2−/− mice were divided into normal chow (NC) and high-fat diet (HFD) groups to create insulin resistance mice model. After 8 weeks the IR model group was then divided into HFD sedentary control and HFD exercise groups (HE). Mice in HE group underwent 6-week treadmill exercise to reveal the effect of exercise training on lipid metabolism in insulin resistance model induced by HFD. We explored the mechanism through which Sestrin2 regulated lipid metabolism in vitro by supplying palmitate, overexpressing or inhibiting SESNs, SHIP2 and JNK in myotubes. Results We found that 6-week exercise training decreased body weight, BMI and fat mass in wild type and SESN2-/- mice after high-fat diet (HFD) feeding. And exercise training decreased the level of plasma glucose, serum insulin, triglycerides and free fatty acids in wild type but not in Sestrin2-/- mice. Lipid droplet in skeletal muscle was also decreased in wild type but did not in Sestrin2-/- mice. Moreover, exercise training increased the proteins expression involved in fatty acid oxidation and decreased the proteins which related to fatty acid de novo synthesis. The results of oil red staining and the change of proteins related to fatty acid de novo synthesis and beta oxidation in myotubes treated with palmitate, Ad-SESN2 and siRNA-Sestrin2 were consisted with the results in vivo, which suggested that Sestrin2 was a key regulator in lipid metabolism. Exercise training increased Sestrin2 expression and reversed up-regulation of SHIP2 and pJNK induced by HFD in wild type mice but not in Sestrin2-/- mice. In parallel, overexpression of Sestrin2 decreased the level of SHIP2 and pJNK induced by palmitate while Sestrin2 knock down by siRNA-Sestrin2 treatment did not change the expression of SHIP2 and pJNK, which suggested that Sestrin2 modulated SHIP2 and JNK in the state of abnormal lipid metabolism. Inhibition of SHIP2 reduced the activity of JNK, increased lipid accumulation and the proteins of fatty acid synthesis after palmitate treatment and over expression of Sestrin2, which suggest that Sestrin2 modulated lipid metabolism through SHIP2/JNK pathway. Conclusions Sestrin2 plays an important role in improving lipid metabolism after exercise training, and Sestrin2 regulates lipid metabolism by SHIP2-JNK pathway in skeletal muscle.

Saturated, but not n-6 polyunsaturated, fatty acids induce insulin resistance: role of intramuscular accumulation of lipid metabolites

2006 ◽  
Vol 100 (5) ◽  
pp. 1467-1474 ◽  
Author(s):  
Jong Sam Lee ◽  
Srijan K. Pinnamaneni ◽  
Su Ju Eo ◽  
In Ho Cho ◽  
Jae Hwan Pyo ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acids ◽  
Insulin Sensitivity ◽  
Polyunsaturated Fatty Acids ◽  
Glucose Uptake ◽  
High Fat ◽  
Insulin Resistant ◽  
L6 Myotubes ◽  
Lipid Metabolites

Consumption of a Western diet rich in saturated fats is associated with obesity and insulin resistance. In some insulin-resistant phenotypes this is associated with accumulation of skeletal muscle fatty acids. We examined the effects of diets high in saturated fatty acids (Sat) or n-6 polyunsaturated fatty acids (PUFA) on skeletal muscle fatty acid metabolite accumulation and whole-body insulin sensitivity. Male Sprague-Dawley rats were fed a chow diet (16% calories from fat, Con) or a diet high (53%) in Sat or PUFA for 8 wk. Insulin sensitivity was assessed by fasting plasma glucose and insulin and glucose tolerance via an oral glucose tolerance test. Muscle ceramide and diacylglycerol (DAG) levels and triacylglycerol (TAG) fatty acids were also measured. Both high-fat diets increased plasma free fatty acid levels by 30%. Compared with Con, Sat-fed rats were insulin resistant, whereas PUFA-treated rats showed improved insulin sensitivity. Sat caused a 125% increase in muscle DAG and a small increase in TAG. Although PUFA also resulted in a small increase in DAG, the excess fatty acids were primarily directed toward TAG storage (105% above Con). Ceramide content was unaffected by either high-fat diet. To examine the effects of fatty acids on cellular lipid storage and glucose uptake in vitro, rat L6 myotubes were incubated for 5 h with saturated and polyunsaturated fatty acids. After treatment of L6 myotubes with palmitate (C16:0), the ceramide and DAG content were increased by two- and fivefold, respectively, concomitant with reduced insulin-stimulated glucose uptake. In contrast, treatment of these cells with linoleate (C18:2) did not alter DAG, ceramide levels, and glucose uptake compared with controls (no added fatty acids). Both 16:0 and 18:2 treatments increased myotube TAG levels (C18:2 vs. C16:0, P < 0.05). These results indicate that increasing dietary Sat induces insulin resistance with concomitant increases in muscle DAG. Diets rich in n-6 PUFA appear to prevent insulin resistance by directing fat into TAG, rather than other lipid metabolites.

Thiazolidinediones enhance skeletal muscle triacylglycerol synthesis while protecting against fatty acid-induced inflammation and insulin resistance

2007 ◽  
Vol 292 (2) ◽  
pp. E485-E493 ◽  
Author(s):  
Mark K. Todd ◽  
Matthew J. Watt ◽  
Jamie Le ◽  
Andrea L. Hevener ◽  
Lorraine P. Turcotte
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Insulin Action ◽  
Dietary Lipid ◽  
Lipid Levels ◽  
High Fat ◽  
Glucose Kinetics ◽  
Triacylglycerol Synthesis ◽  
Male Wistar Rats

In the present investigation, we studied the effects of thiazolidinedione (TZD) treatment on insulin-stimulated fatty acid (FA) and glucose kinetics in perfused muscle from high-fat (HF)-fed rats. We tested the hypothesis that TZDs prevent FA-induced insulin resistance by attenuating proinflammatory signaling independently of myocellular lipid levels. Male Wistar rats were assigned to one of three 3-wk dietary groups: control chow fed (CON), 65% HF diet (HFD), or TZD- (troglitazone or rosiglitazone) enriched HF diet (TZD + HFD). TZD treatment led to a significant increase in plasma membrane content of CD36 protein in muscle (red: P = 0.01, and white: P = 0.001) that correlated with increased FA uptake (45%, P = 0.002) and triacylglycerol (TG) synthesis (46%, P = 0.03) during the perfusion. Importantly, whereas HF feeding caused increased basal TG ( P = 0.047), diacylglycerol ( P = 0.002), and ceramide ( P = 0.01) levels, TZD treatment only prevented the increase in muscle ceramide. In contrast, all of the muscle inflammatory markers altered by HF feeding (↑NIK protein content, P = 0.009; ↑IKKβ activity, P = 0.006; ↓IκB-α protein, P = 0.03; and ↑JNK phosphorylation, P = 0.003) were completely normalized by TZD treatment. Consistent with this, HFD-induced decrements in insulin action were also prevented by TZD treatment. Thus our findings support the notion that TZD treatment causes increased FA uptake and TG accumulation in skeletal muscle under insulin-stimulated conditions. Despite this, TZDs suppress the inflammatory response to dietary lipid overload, and it is this mechanism that correlates strongly with insulin sensitivity.

scholarly journals LMNA Mutations, Skeletal Muscle Lipid Metabolism, and Insulin Resistance

2010 ◽  
Vol 95 (4) ◽  
pp. 1634-1643 ◽  
Author(s):  
Michael Boschmann ◽  
Stefan Engeli ◽  
Cedric Moro ◽  
Angelika Luedtke ◽  
Frauke Adams ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Lipid Oxidation ◽  
Exercise Intolerance ◽  
Intrinsic Defect ◽  
Lamin A ◽  
Glucose Ingestion

Abstract Context: Type 2 familial partial lipodystrophy (FPLD) is an autosomal-dominant lamin A/C-related disease associated with exercise intolerance, muscular pain, and insulin resistance. The symptoms may all be explained by defective metabolism; however, metabolism at the tissue level has not been investigated. Objective: We hypothesized that in FPLD, insulin resistance and impaired aerobic exercise capacity are explained by a common underlying mechanism, presumably a muscular metabolic defect. Patients and Methods: Carbohydrate and lipid metabolism was studied on 10 FPLD patients, one patient with limb-girdle muscular dystrophy (LGMD1B, a different lamin A/C disease), and 10 healthy control subjects before and during an oral glucose tolerance test by indirect calorimetry and im microdialysis. Muscle biopsies were taken for in vitro studies. Results: We observed marked increased skeletal muscle fatty acid β-oxidation rate in vitro and in vivo, even after glucose ingestion in FPLD patients. However, fatty acid oxidation was largely incomplete and accompanied by increased ketogenesis. The lipid oxidation abnormality was associated with impaired glucose disposition through reduction in glucose oxidation, rather than decreased cellular glucose uptake. A microarray showed down-regulation of complex I respiratory chain, glycolysis, and nuclear transport genes. Although not overtly insulin resistant, the LGMD1B patient showed similar metabolic derangements as the FPLD patients. Conclusions: Our study suggests imbalance between lipid oxidation and oxidative glucose metabolism in FPLD and LGMD1B patients. The observation suggests an intrinsic defect in skeletal muscle metabolism due to lamin A/C dysfunction. The metabolic FPLD phenotype likely results from this intrinsic defect combined with lipodystrophic “lipid pressure” due to decreased adipose tissue lipid storage capacity.

Mitochondrial function and dysfunction in exercise and insulin resistanceThis paper article is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic Machines, and has undergone the Journal’s usual peer review process.

2009 ◽  
Vol 34 (3) ◽  
pp. 440-446 ◽  
Author(s):  
Graham P. Holloway
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Fatty Acid Oxidation ◽  
Peer Review Process ◽  
Acid Oxidation ◽  
Fatty Acid Transport ◽  
Acid Transport ◽  
Mitochondrial Content ◽  
Mitochondrial Fatty Acid

Fatty acid translocase (FAT/CD36) represents a novel flexible regulatory system, influencing rates of mitochondrial fatty acid metabolism in both human and rodent skeletal muscle. During exercise, the subcellular redistribution of FAT/CD36 provides a mechanism to increase not only plasma membrane fatty acid transport, but also mitochondrial fatty acid oxidation. This FAT/CD36-mediated coordination of long chain fatty acid (LCFA) transport and oxidation is an intriguing model in the context of insulin resistance. It was believed for almost a decade that reductions in fatty acid oxidation increased intramuscular lipids, thereby contributing to insulin resistance. A reduction in mitochondrial content may reduce the capacity of skeletal muscle LCFA oxidation; however, work from my laboratory has shown that, in some insulin-resistant muscles, mitochondrial content and fatty acid oxidation are both increased, yet these muscles accumulate lipids because of a considerably greater increase in fatty acid transport. Therefore, an alternative model is being considered, in which the balance between LCFA uptake and oxidation is a determining factor in the development of insulin resistance. A permanent redistribution of the LCFA transport protein FAT/CD36 to the sarcolemmal has been consistently found, which results in an increased rate of LCFA transport. This work suggests that the accumulation of skeletal muscle lipids, regardless of changes in mitochondria, is attributable to an increased rate of LCFA transport that exceeds the capacity for oxidation.

scholarly journals Rapid development of systemic insulin resistance with overeating is not accompanied by robust changes in skeletal muscle glucose and lipid metabolism

2013 ◽  
Vol 38 (5) ◽  
pp. 512-519 ◽  
Author(s):  
Andrea S. Cornford ◽  
Alexander Hinko ◽  
Rachael K. Nelson ◽  
Ariel L. Barkan ◽  
Jeffrey F. Horowitz
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Lipid Metabolism ◽  
Insulin Sensitivity ◽  
Lipid Accumulation ◽  
Rapid Development ◽  
Insulin Response ◽  
Whole Body ◽  
Muscle Lipid ◽  
Wet Weight

Prolonged overeating and the resultant weight gain are clearly linked with the development of insulin resistance and other cardiometabolic abnormalities, but adaptations that occur after relatively short periods of overeating are not completely understood. The purpose of this study was to characterize metabolic adaptations that may accompany the development of insulin resistance after 2 weeks of overeating. Healthy, nonobese subjects (n = 9) were admitted to the hospital for 2 weeks, during which time they ate ∼4000 kcals·day−1 (70 kcal·kg−1 fat free mass·day−1). Insulin sensitivity was estimated during a meal tolerance test, and a muscle biopsy was obtained to assess muscle lipid accumulation and protein markers associated with insulin resistance, inflammation, and the regulation of lipid metabolism. Whole-body insulin sensitivity declined markedly after 2 weeks of overeating (Matsuda composite index: 8.3 ± 1.3 vs. 4.6 ± 0.7, p < 0.05). However, muscle markers of insulin resistance and inflammation (i.e., phosphorylation of IRS-1-Ser312, Akt-Ser473, and c-Jun N-terminal kinase) were not altered by overeating. Intramyocellular lipids tended to increase after 2 weeks of overeating (triacylglyceride: 7.6 ± 1.6 vs. 10.0 ± 1.8 nmol·mg−1 wet weight; diacylglyceride: 104 ± 10 vs. 142 ± 23 pmol·mg−1 wet weight) but these changes did not reach statistical significance. Overeating induced a 2-fold increase in 24-h insulin response (area under the curve (AUC); p < 0.05), with a resultant ∼35% reduction in 24-h plasma fatty acid AUC (p < 0.05). This chronic reduction in circulating fatty acids may help explain the lack of a robust increase in muscle lipid accumulation. In summary, our findings suggest alterations in skeletal muscle metabolism may not contribute meaningfully to the marked whole-body insulin resistance observed after 2 weeks of overeating.

scholarly journals Retinoic acid exerts sexually dimorphic effects over muscle energy metabolism and function

2021 ◽  
Author(s):  
Yaxin Zhao ◽  
Marta Vuckovic ◽  
Hong Sik Yoo ◽  
Nina Fox ◽  
Adrienne Rodriguez ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Fatty Acid ◽  
Electron Transport Chain ◽  
Energy Use ◽  
Acid Oxidation ◽  
Retinol Dehydrogenase ◽  
Transport Chain ◽  
Muscle Energy ◽  
Glut1 Mrna

Among others, the retinol dehydrogenase Rdh10 catalyzes the rate-limiting reaction that converts retinol into retinoic acid (RA), an autacoid that regulates energy balance and suppresses adiposity. Relative to WT, Rdh10+/- males experienced reduced fatty-acid oxidation, glucose intolerance and insulin resistance. Running endurance decreased 40%. Rdh10+/- females increased reliance on fatty acid oxidation and did not experience glucose intolerance nor insulin resistance. Running endurance improved 2.2-fold. Estrogen increased, revealed by a 40% increase in uterine weight. Because skeletal muscle energy use restricts adiposity and insulin resistance, we assessed the mixed fiber type gastrocnemius muscle (GM) to determine the effects of endogenous RA on muscle metabolism in vivo. RA in Rdh10+/- male GM decreased 38% relative to WT. TAG content increased 1.7-fold. Glut1 mRNA and glucose decreased >30%. Rdh10+/- male GM had impaired electron transport chain activity, and a 60% reduction in fasting ATP. The share of oxidative fibers increased, as did expression of the myogenic transcription factors Myog and Myf5. Centralized nuclei increased 5-fold in fibersindicating muscle malady or repair. In Rdh10+/- female GM, RA decreased only 17%, due to a 1.8-fold increase in the estrogen-induced retinol dehydrogenase, Dhrs9. Rdh10+/- female GM did not amass TAG, increase oxidative fibers, decrease Glut1 mRNA or glucose, nor increase centralized nuclei. Expression of Myog and Myf5 decreased. Electron transport chain activity increased, elevating fasting ATP >3-fold. Thus, small decreases in skeletal muscle RA affect whole body energy use, insulin resistance and adiposity, in part through estrogen-related sexual dimorphic effects on mitochondria function.

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