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.

scholarly journals Combined effect of canagliflozin and exercise training on high-fat diet-fed mice

2020 ◽  
Vol 318 (4) ◽  
pp. E492-E503
Author(s):  
Kenichi Tanaka ◽  
Hirokazu Takahashi ◽  
Sayaka Katagiri ◽  
Kazuyo Sasaki ◽  
Yujin Ohsugi ◽  
...  
Keyword(s):  
Gene Expression ◽  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Exercise Training ◽  
Fatty Liver ◽  
High Fat Diet ◽  
Characteristic Change ◽  
High Fat ◽  
Nonalcoholic Fatty Liver ◽  
Sodium Glucose Cotransporter

Sodium-glucose cotransporter 2 inhibitors (SGLT2is) have been reported to improve obesity, diabetes, and nonalcoholic fatty liver disease (NAFLD) in addition to exercise training, whereas the combined effects remain to be elucidated fully. We investigated the effect of the combination of the SGLT2i canagliflozin (CAN) and exercise training in high-fat diet-induced obese mice. High-fat diet-fed mice were housed in normal cages (sedentary; Sed) or wheel cages (WCR) with or without CAN (0.03% of diet) for 4 wk. The effects on obesity, glucose metabolism, and hepatic steatosis were evaluated in four groups (Control/Sed, Control/WCR, CAN/Sed, and CAN/WCR). Numerically additive improvements were found in body weight, body fat mass, blood glucose, glucose intolerance, insulin resistance, and the fatty liver of the CAN/WCR group, whereas CAN increased food intake and reduced running distance. Exercise training alone, CAN alone, or both did not change the weight of skeletal muscle, but microarray analysis showed that each resulted in a characteristic change of gene expression in gastrocnemius muscle. In particular, in the CAN/WCR group, there was acceleration of the angiogenesis pathway and suppression of the adipogenesis pathway compared with the CAN/Sed group. In conclusion, the combination of an SGLT2i and exercise training improves obesity, insulin resistance, and NAFLD in an additive manner. Changes of gene expression in skeletal muscle may contribute, at least in part, to the improvement of obesity and insulin sensitivity.

scholarly journals CD44 contributes to hyaluronan-mediated insulin resistance in skeletal muscle of high-fat-fed C57BL/6 mice

2019 ◽  
Vol 317 (6) ◽  
pp. E973-E983 ◽  
Author(s):  
Annie Hasib ◽  
Chandani K. Hennayake ◽  
Deanna P. Bracy ◽  
Aimée R. Bugler-Lamb ◽  
Louise Lantier ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
High Fat Diet ◽  
Critical Role ◽  
Chow Diet ◽  
Wild Type ◽  
High Fat ◽  
Insulin Resistant ◽  
Beneficial Effects

Extracellular matrix hyaluronan is increased in skeletal muscle of high-fat-fed insulin-resistant mice, and reduction of hyaluronan by PEGPH20 hyaluronidase ameliorates diet-induced insulin resistance (IR). CD44, the main hyaluronan receptor, is positively correlated with type 2 diabetes. This study determines the role of CD44 in skeletal muscle IR. Global CD44-deficient ( cd44−/−) mice and wild-type littermates ( cd44+/+) were fed a chow diet or 60% high-fat diet for 16 wk. High-fat-fed cd44−/− mice were also treated with PEGPH20 to evaluate its CD44-dependent action. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp (ICv). High-fat feeding increased muscle CD44 protein expression. In the absence of differences in body weight and composition, despite lower clamp insulin during ICv, the cd44−/− mice had sustained glucose infusion rate (GIR) regardless of diet. High-fat diet-induced muscle IR as evidenced by decreased muscle glucose uptake (Rg) was exhibited in cd44+/+ mice but absent in cd44−/− mice. Moreover, gastrocnemius Rg remained unchanged between genotypes on chow diet but was increased in high-fat-fed cd44−/− compared with cd44+/+ when normalized to clamp insulin concentrations. Ameliorated muscle IR in high-fat-fed cd44−/− mice was associated with increased vascularization. In contrast to previously observed increases in wild-type mice, PEGPH20 treatment in high-fat-fed cd44−/− mice did not change GIR or muscle Rg during ICv, suggesting a CD44-dependent action. In conclusion, genetic CD44 deletion improves muscle IR, and the beneficial effects of PEGPH20 are CD44-dependent. These results suggest a critical role of CD44 in promoting hyaluronan-mediated muscle IR, therefore representing a potential therapeutic target for diabetes.

scholarly journals L-Carnitine Is Involved in Hyperbaric Oxygen-Mediated Therapeutic Effects in High Fat Diet-Induced Lipid Metabolism Dysfunction

Molecules ◽  
2020 ◽  
Vol 25 (1) ◽  
pp. 176 ◽  
Author(s):  
Junhua Yuan ◽  
Qixiao Jiang ◽  
Limin Song ◽  
Yuan Liu ◽  
Manwen Li ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Hyperbaric Oxygen ◽  
High Fat Diet ◽  
Therapeutic Effects ◽  
Human Beings ◽  
High Fat ◽  
Adipose Tissues ◽  
Expression Levels

Lipid metabolism dysfunction and obesity are serious health issues to human beings. The current study investigated the effects of hyperbaric oxygen (HBO) against high fat diet (HFD)-induced lipid metabolism dysfunction and the roles of L-carnitine. C57/B6 mice were fed with HFD or normal chew diet, with or without HBO treatment. Histopathological methods were used to assess the adipose tissues, serum free fatty acid (FFA) levels were assessed with enzymatic methods, and the endogenous circulation and skeletal muscle L-carnitine levels were assessed with liquid chromatography-tandem mass spectrometry (LC-MS/MS). Additionally, western blotting was used to assess the expression levels of PPARα, CPT1b, pHSL/HSL, and UCP1. HFD treatment increased body/adipose tissue weight, serum FFA levels, circulation L-carnitines and decreased skeletal muscle L-carnitine levels, while HBO treatment alleviated such changes. Moreover, HFD treatment increased fatty acid deposition in adipose tissues and decreased the expression of HSL, while HBO treatment alleviated such changes. Additionally, HFD treatment decreased the expression levels of PPARα and increased those of CPT1b in skeletal muscle, while HBO treatment effectively reverted such changes as well. In brown adipose tissues, HFD increased the expression of UCP1 and the phosphorylation of HSL, which was abolished by HBO treatment as well. In summary, HBO treatment may alleviate HFD-induced fatty acid metabolism dysfunction in C57/B6 mice, which seems to be associated with circulation and skeletal muscle L-carnitine levels and PPARα expression.

Genetically increasing flux through β-oxidation in skeletal muscle increases mitochondrial reductive stress and glucose intolerance

2021 ◽  
Author(s):  
Cody D. Smith ◽  
Chein-Te Lin ◽  
Shawna L. McMillin ◽  
Luke A. Weyrauch ◽  
Cameron Alan Schmidt ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Fatty Acid ◽  
Glucose Tolerance ◽  
Glucose Intolerance ◽  
High Fat Diet ◽  
Whole Body ◽  
Acid Oxidation ◽  
Wild Type ◽  
High Fat ◽  
Redox Environment

Elevated mitochondrial H2O2 emission and an oxidative shift in cytosolic redox environment have been linked to high fat diet-induced insulin resistance in skeletal muscle. To test specifically whether increased flux through mitochondrial fatty acid oxidation, in the absence of elevated energy demand, directly alters mitochondrial function and redox state in muscle, two genetic models characterized by increased muscle β-oxidation flux were studied. In mice overexpressing peroxisome proliferator activated receptor-α in muscle (MCK-PPARα), lipid supported mitochondrial respiration, membrane potential (ΔΨm) and H2O2 production rate (JH2O2) were increased, which coincided with a more oxidized cytosolic redox environment, reduced muscle glucose uptake, and whole-body glucose intolerance despite an increased rate of energy expenditure. Similar results were observed in lipin-1 deficient, fatty-liver dystrophic mice, another model characterized by increased β-oxidation flux and glucose intolerance. Crossing MCAT (mitochondrial-targeted catalase) with MCK-PPARα mice normalized JH2O2 production, redox environment and glucose tolerance, but surprisingly both basal and absolute insulin-stimulated rates of glucose uptake in muscle remained depressed. Also surprising, when placed on a high fat diet MCK-PPARα mice were characterized by much lower whole body, fat and lean mass as well as improved glucose tolerance relative to wild-type mice, providing additional evidence that overexpression of PPARα in muscle imposes more extensive metabolic stress than experienced by wild-type mice on a high fat diet. Overall, the findings suggest that driving an increase in skeletal muscle fatty acid oxidation in the absence of metabolic demand imposes mitochondrial reductive stress and elicits multiple counterbalance metabolic responses in attempt to restore bioenergetic homeostasis.

scholarly journals Mogroside V Protects against Hepatic Steatosis in Mice on a High-Fat Diet and LO2 Cells Treated with Free Fatty Acids via AMPK Activation

2020 ◽  
Vol 2020 ◽  
pp. 1-11
Author(s):  
Linghuan Li ◽  
Wanfang Zheng ◽  
Can Wang ◽  
Jiameng Qi ◽  
Hanbing Li
Keyword(s):  
Fatty Acids ◽  
Fatty Acid ◽  
Lipid Metabolism ◽  
Free Fatty Acids ◽  
Mrna Expression ◽  
Hepatic Steatosis ◽  
High Fat Diet ◽  
De Novo ◽  
Acid Oxidation ◽  
High Fat

Previous studies presented various beneficial effects of mogrosides extract from Siraitia grosvenorii, which has been included in the list of Medicine Food Homology Species in China. Mogroside V (MV) is one of the main ingredients in mogrosides extract; however, whether and how MV improves impaired lipid metabolism in the liver remains to be elucidated. Herein, we investigated the therapeutic effects of mogroside V upon hepatic steatosis in vivo and in vitro and explored the underlying mechanisms. The results showed that MV significantly ameliorated hepatic steatosis in high-fat diet- (HFD-) fed mice. Furthermore, the increased protein expression of PPAR-γ, SREBP-1, and FASN and mRNA expression of pparg, srebp1, scd1, and fasn in the liver in HFD-fed mice, which contribute to de novo lipogenesis, were dose-dependently reversed by MV treatment. Meanwhile, MV counteracted the suppressed expression of PPAR-α and CPT-1A and mRNA expression of atgl, hsl, ppara, and cpt1a, thus increasing lipolysis and fatty acid oxidation. In addition, in free fatty acids- (FFAs-) incubated LO2 cells MV downregulated de novo lipogenesis and upregulated lipolysis and fatty acid oxidation, thereby attenuating lipid accumulation, which was significantly abrogated by treatment with Compound C, an inhibitor of AMP-activated protein kinase (AMPK). Taken together, these results suggested that MV exerted a pronounced effect upon improving hepatic steatosis through regulating the disequilibrium of lipid metabolism in the liver via an AMPK-dependent pathway, providing a potential lead compound candidate for preventing nonalcoholic fatty liver disease.

scholarly journals Swimming Exercise Protects against Insulin Resistance via Regulating Oxidative Stress through Nox4 and AKT Signaling in High-Fat Diet-Fed Mice

2020 ◽  
Vol 2020 ◽  
pp. 1-9 ◽  
Author(s):  
Jie Qi ◽  
Xue Luo ◽  
Zhichao Ma ◽  
Bo Zhang ◽  
Shuyan Li ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Exercise Training ◽  
High Fat Diet ◽  
Akt Signaling ◽  
Oxygen Species ◽  
Akt Signaling Pathway ◽  
Insulin Stimulation ◽  
High Fat ◽  
Nadph Oxidase 4

Nonpharmaceutical therapies such as exercise training and diet intervention are widely used for the treatment of insulin resistance (IR). Although the skeletal muscle is the major peripheral tissue of glucose metabolism under insulin stimulation, the mechanism underlying muscle IR is poorly understood. Using a high-fat diet-induced IR mouse model, we here show that NADPH oxidase 4 (Nox4) upregulation mediates the production of reactive oxygen species (ROS) that causes metabolic syndrome featuring IR. The Nox4 expression level was markedly elevated in IR mice, and Nox4 overexpression was sufficient to trigger IR. Conversely, downregulation of Nox4 expression through exercise training prevented diet-induced IR by reducing the production of ROS and enhancing the AKT signaling pathway. Thus, this study indicates that exercise might improve IR through a reduction of Nox4-induced ROS in the skeletal muscle and enhancement of AKT signal transduction.

AMPK-α2 is involved in exercise training-induced adaptations in insulin-stimulated metabolism in skeletal muscle following high-fat diet

2014 ◽  
Vol 117 (8) ◽  
pp. 869-879 ◽  
Author(s):  
Marcia J. Abbott ◽  
Lorraine P. Turcotte
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Exercise Training ◽  
High Fat Diet ◽  
Citrate Synthase ◽  
Wheel Running ◽  
Dominant Negative ◽  
Standard Diet ◽  
High Fat ◽  
Palmitate Uptake

AMP-activated protein kinase (AMPK) has been studied extensively and postulated to be a target for the treatment and/or prevention of metabolic disorders such as insulin resistance. Exercise training has been deemed a beneficial treatment for obesity and insulin resistance. Furthermore, exercise is a feasible method to combat high-fat diet (HFD)-induced alterations in insulin sensitivity. The purpose of this study was to determine whether AMPK-α2 activity is required to gain beneficial effects of exercise training with high-fat feeding. Wild-type (WT) and AMPK-α2 dominant-negative (DN) male mice were fed standard diet (SD), underwent voluntary wheel running (TR), fed HFD, or trained with HFD (TR + HFD). By week 6, TR, irrespective of genotype, decreased blood glucose and increased citrate synthase activity in both diet groups and decreased insulin levels in HFD groups. Hindlimb perfusions were performed, and, in WT mice with SD, TR increased insulin-mediated palmitate uptake (76.7%) and oxidation (>2-fold). These training-induced changes were not observed in the DN mice. With HFD, TR decreased palmitate oxidation (61–64%) in both WT and DN and increased palmitate uptake (112%) in the WT with no effects on palmitate uptake in the DN. With SD, TR increased ERK1/2 and JNK1/2 phosphorylation, regardless of genotype. With HFD, TR reduced JNK1/2 phosphorylation, regardless of genotype, carnitine palmitoyltransferase 1 expression in WT, and CD36 expression in both DN and WT. These data suggest that low AMPK-α2 signaling disrupts, in part, the exercise training-induced adaptations in insulin-stimulated metabolism in skeletal muscle following HFD.

scholarly journals High-Fat Diet-Mediated Lipotoxicity and Insulin Resistance Is Related to Impaired Lipase Expression in Mouse Skeletal Muscle

Endocrinology ◽  
2013 ◽  
Vol 154 (4) ◽  
pp. 1444-1453 ◽  
Author(s):  
Pierre-Marie Badin ◽  
Isabelle K. Vila ◽  
Katie Louche ◽  
Aline Mairal ◽  
Marie-Adeline Marques ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Protein Kinase ◽  
Protein Content ◽  
Insulin Signaling ◽  
High Fat Diet ◽  
Whole Body ◽  
Wild Type ◽  
High Fat ◽  
Lipase Expression

Abstract Elevated expression/activity of adipose triglyceride lipase (ATGL) and/or reduced activity of hormone-sensitive lipase (HSL) in skeletal muscle are causally linked to insulin resistance in vitro. We investigated here the effect of high-fat feeding on skeletal muscle lipolytic proteins, lipotoxicity, and insulin signaling in vivo. Five-week-old C3H mice were fed normal chow diet (NCD) or 45% kcal high-fat diet (HFD) for 4 weeks. Wild-type and HSL knockout mice fed NCD were also studied. Whole-body and muscle insulin sensitivity, as well as lipolytic protein expression, lipid levels, and insulin signaling in skeletal muscle, were measured. HFD induced whole-body insulin resistance and glucose intolerance and reduced skeletal muscle glucose uptake compared with NCD. HFD increased skeletal muscle total diacylglycerol (DAG) content, protein kinase Cθ and protein kinase Cϵ membrane translocation, and impaired insulin signaling as reflected by a robust increase of basal Ser1101 insulin receptor substrate 1 phosphorylation (2.8-fold, P < .05) and a decrease of insulin-stimulated v-Akt murine thymoma viral oncogene homolog Ser473 (−37%, P < .05) and AS160 Thr642 (−47%, P <.01) phosphorylation. We next showed that HFD strongly reduced HSL phosphorylation at Ser660. HFD significantly up-regulated the muscle protein content of the ATGL coactivator comparative gene identification 58 and triacylglycerol hydrolase activity, despite a lower ATGL protein content. We further show a defective skeletal muscle insulin signaling and DAG accumulation in HSL knockout compared with wild-type mice. Together, these data suggest a pathophysiological link between altered skeletal muscle lipase expression and DAG-mediated insulin resistance in mice.

scholarly journals Dietary Glycotoxins Impair Hepatic Lipidemic Profile in Diet-Induced Obese Rats Causing Hepatic Oxidative Stress and Insulin Resistance

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
C. Neves ◽  
T. Rodrigues ◽  
J. Sereno ◽  
C. Simões ◽  
J. Castelhano ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Insulin Resistance ◽  
Fatty Acid ◽  
High Fat Diet ◽  
De Novo ◽  
Liver Lipid ◽  
Lipid Fraction ◽  
De Novo Lipogenesis ◽  
High Fat ◽  
Obese Rats

Nonalcoholic fatty liver disease (NAFLD) is caused by excessive liver lipid accumulation, but insulin resistance is specifically associated with impaired lipid saturation, oxidation, and storage (esterification), besides increased de novo lipogenesis. We hypothesized that dietary glycotoxins could impair hepatic lipid metabolism in obesity contributing to lipotoxicity-driven insulin resistance and thus to the onset of nonalcoholic steatohepatitis (NASH). In diet-induced obese rats with methylglyoxal-induced glycation, magnetic resonance spectroscopy, mass spectrometry, and gas chromatography were used to assess liver composition in fatty acyl chains and phospholipids. High-fat diet-induced obesity increased liver lipid fraction and suppressed de novo lipogenesis but did not change fatty acid esterification and saturation or insulin sensitivity. Despite a similar increase in total lipid fraction when supplementing the high-fat diet with dietary glycotoxins, impairment in the suppression of de novo lipogenesis and decreased fatty acid unsaturation and esterification were observed. Moreover, glycotoxins also decreased polyunsaturated cardiolipins and caused oxidative stress, portal inflammation, and insulin resistance in high-fat diet-induced obese rats. Dietary glycated products do not change total lipid levels in the liver of obese rats but dramatically modify the lipidemic profile, leading to oxidative stress, hepatic lipotoxicity, and insulin resistance in obesity and thus contribute to the onset of NASH.

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