Diet-induced Insulin Resistance In Skeletal Muscle Research Articles

High temperature ameliorates high-fat diet-induced obesity by promoting ceramide breakdown in skeletal muscle tissue

Abstract Obesity is considered an epidemic often accompanied by insulin resistance (IR). Heat treatment (HT) has been shown to prevent high-fat diet-induced IR in skeletal muscle, but the underlying mechanisms are poorly understood. In this study, we discovered that high temperature alleviated the hallmarks of obesity by promoting glycogen synthesis and lowering blood glucose levels in skeletal muscle tissue (SMT). Additionally, HT maintained the decay phase of heat shock factor 1 (HSF1), leading to the activation of gene expression of heat shock proteins (HSPs), which contributed to the alleviation of IR in SMT of diet-induced obese (DIO) mice. Metabolomics and lipidomics analyses showed that HT promoted ceramide (Cer) breakdown, resulting in an elevation of both sphingomyelin (SM) and sphingosine, which further contributed to the amelioration of IR in SMT of DIO mice. Importantly, the increase in sphingosine was attributed to the heightened expression of the acid ceramidase N-acylsphingosine amidohydrolase 1 (ASAH1), and the inhibition of ASAH1 attenuated HT-relieved IR in SMT of DIO mice. Surprisingly, high temperature increased the composition of Cer and cholesteryl ester in lipid droplets of skeletal muscle cells. This not only helped alleviate IR but also prevented lipotoxicity in SMT of DIO mice. These findings revealed a previously unknown connection between a high-temperature environment and sphingolipid metabolism in obesity, suggesting that high temperature can improve IR by promoting Cer catabolism in SMT of obese mice.

Metformin alleviates long-term high-fructose diet-induced skeletal muscle insulin resistance in rats by regulating purine nucleotide cycle

Nutrient excess caused by excessive fructose intake can lead to insulin resistance and dyslipidemia, which further causes the development of metabolic syndrome. Metformin is a well-known AMPK activator widely used for the treatment of metabolic syndrome, while the mechanism of AMPK activation remains unclear. The present study aimed to investigate the pharmacological effects of metformin on fructose-induced insulin resistance rat, and the potential mechanism underlying AMPK activation in skeletal muscle tissue. Results indicated that metformin significantly ameliorated features of insulin resistance, including body weight, Lee's index, hyperinsulinemia, dyslipidemia, insulin intolerance and pancreatic damage. Moreover, treatment with metformin attenuated the inflammatory response in serum and enhanced the antioxidant capacity in skeletal muscle tissue. The therapeutic effects of metformin on fructose-induced insulin resistance may be related to the activation of AMPK to regulate Nrf2 pathway and mitochondrial abnormality. Additionally, metformin suppressed the expression of adenosine monophosphate deaminase 1 (AMPD1) and up-regulated the expression of adenylosuccinate synthetase (ADSS) in the purine nucleotide cycle (PNC), which facilitated the increase of AMP level and the ratio of AMP/ATP. Therefore, we proposed a novel mechanism that metformin activated AMPK via increasing AMP by regulating the expression of AMPD1 and ADSS in PNC pathway.

Cytosolic lipid excess-induced mitochondrial dysfunction is the cause or effect of high fat diet-induced skeletal muscle insulin resistance: a molecular insight.

Mitochondria play a central role in the energy homeostasis in eukaryotic cells by generating ATP via oxidative metabolism of nutrients. Excess lipid accumulation and impairments in mitochondrial function have been considered as putative mechanisms for the pathogenesis of skeletal muscle insulin resistance. Accumulation of lipids in tissues occurs due to either excessive fatty acid uptake, decreased fatty acid utilization or both. Consequently, elevated levels cytosolic lipid metabolites, triglycerides, diacylglycerol and ceramides have been demonstrated to adversely affect glucose homeostasis. Several recent studies indicate that reduced insulin-stimulated ATP synthesis and reduced expression of mitochondrial enzymes and PPAR-γ coactivator, in high fat feeding (lipid overload) are associated with insulin resistance. Despite the fact, few notable studies suggest mitochondrial dysfunction is prevalent in type 2 diabetes mellitus; it is still not clear whether the defects in mitochondrial function are the cause of insulin resistance or the consequential effects of insulin resistance itself. Thus, there is a growing interest in understanding the intricacies of mitochondrial function and its association with cytosolic lipid excess. This review therefore critically examines the molecular cascades linking cytosolic lipid excess and mitochondrial dysfunction in the pathogenesis of high fat diet-induced insulin resistance in skeletal muscle. The sequential processes following the excess intake of high fat diet in skeletal muscle includes, accumulation of cytosolic fatty acids, increased production of reactive oxygen species, mutations and ageing, and decreased mitochondrial biogenesis. The consequent mitochondrial dysfunction is then leading to decreased β-oxidation, respiratory functions and glycolysis and increased glucolipotoxicity. These events collectively induce the insulin resistance in skeletal muscle.

PDK4 Augments ER-Mitochondria Contact to Dampen Skeletal Muscle Insulin Signaling During Obesity.

Mitochondria-associated endoplasmic reticulum membrane (MAM) is a structural link between mitochondria and endoplasmic reticulum (ER). MAM regulates Ca2+ transport from the ER to mitochondria via an IP3R1-GRP75-VDAC1 complex–dependent mechanism. Excessive MAM formation may cause mitochondrial Ca2+ overload and mitochondrial dysfunction. However, the exact implication of MAM formation in metabolic syndromes remains debatable. Here, we demonstrate that PDK4 interacts with and stabilizes the IP3R1-GRP75-VDAC1 complex at the MAM interface. Obesity-induced increase in PDK4 activity augments MAM formation and suppresses insulin signaling. Conversely, PDK4 inhibition dampens MAM formation and improves insulin signaling by preventing MAM-induced mitochondrial Ca2+ accumulation, mitochondrial dysfunction, and ER stress. Furthermore, Pdk4−/− mice exhibit reduced MAM formation and are protected against diet-induced skeletal muscle insulin resistance. Finally, forced formation and stabilization of MAMs with synthetic ER–mitochondria linker prevented the beneficial effects of PDK4 deficiency on insulin signaling. Overall, our findings demonstrate a critical mediatory role of PDK4 in the development of skeletal muscle insulin resistance via enhancement of MAM formation.

COMP-angiopoietin-1 enhances skeletal muscle blood flow and insulin sensitivity in mice

To test whether chronic enhanced blood flow alters insulin-stimulated glucose uptake, we measured skeletal muscle glucose uptake in chow-fed and high-fat-fed mice injected with adenovirus containing modified angiopoietin-1, COMP-Ang1, via euglycemic-hyperinsulinemic clamp. Blood flow rates and platelet endothelial cell adhesion molecule-1 positive endothelial cells in the hindlimb skeletal muscle were elevated in COMP-Ang1 compared with control LacZ. Whole body glucose uptake and whole body glycogen/lipid synthesis were elevated in COMP-Ang1 compared with LacZ in chow diet. High-fat diet significantly reduced whole body glucose uptake and whole body glycolysis in LacZ mice, whereas high-fat-fed COMP-Ang1 showed a level of whole body glucose uptake that was comparable with chow-fed LacZ and showed increased glucose uptake compared with high-fat-fed LacZ. Glucose uptake and glycolysis in gastrocnemius muscle of chow-fed COMP-Ang1 were increased compared with chow-fed LacZ. High-fat diet-induced whole body insulin resistance in the LacZ was mostly due to approximately 40% decrease in insulin-stimulated glucose uptake in skeletal muscle. In contrast, COMP-Ang1 prevented diet-induced skeletal muscle insulin resistance compared with high-fat-fed LacZ. Akt phosphorylation in skeletal muscle was increased in COMP-Ang1 compared with LacZ in both chow-fed and high-fat-fed groups. These results suggest that increased blood flow by COMP-Ang1 increases insulin-stimulated glucose uptake and prevents high-fat diet-induced insulin resistance in skeletal muscle.

Resistance training enhances components of the insulin signaling cascade in normal and high-fat-fed rodent skeletal muscle.

Our laboratory recently reported that chronic resistance training (RT) improved insulin-stimulated glucose transport in normal rodent skeletal muscle, owing, in part, to increased GLUT-4 protein concentration (Yaspelkis BB III, Singh MK, Trevino B, Krisan AD, and Collins DE. Acta Physiol Scand 175: 315-323, 2002). However, it remained to be determined whether these improvements resulted from alterations in the insulin signaling cascade as well. In addition, the possibility existed that RT might improve skeletal muscle insulin resistance. Thirty-two male Sprague-Dawley rats were assigned to four groups: control diet (Con)-sedentary (Sed); Con-RT; high-fat diet (HF)-Sed; and HF-RT. Animals consumed their respective diets for 9 wk; then RT animals performed 12 wk of training (3 sets, 10 repetitions at 75% one-repetition maximum, 3x/wk). Animals remained on their dietary treatments over the 12-wk period. After the training period, animals were subjected to hindlimb perfusions. Insulin-stimulated insulin receptor substrate-1-associated phosphatidylinositol-3 kinase activity was enhanced in the red gastrocnemius and quadriceps of Con-RT and HF-RT animals. Atypical PKC-zeta/lambda and Akt activities were reduced in HF-Sed and normalized in HF-RT animals. Resistance training increased GLUT-4 protein concentration in red gastrocnemius and quadriceps of Con-RT and HF-RT animals. No differences were observed in total protein concentrations of insulin receptor substrate-1, Akt, atypical PKC-zeta/lambda, or phosphorylation of Akt. Collectively, these findings suggest that resistance training increases insulin-stimulated carbohydrate metabolism in normal skeletal muscle and reverses high-fat diet-induced skeletal muscle insulin resistance by altering components of both the insulin signaling cascade and glucose transporter effector system.

Chronic leptin treatment enhances insulin-stimulated glucose disposal in skeletal muscle of high-fat fed rodents

The aim of this investigation was to evaluate if chronic leptin administration corrects high fat diet-induced skeletal muscle insulin resistance, in part, by enhancing rates of glucose disposal and if the improvements are accounted for by alterations in components of the insulin-signaling cascade. Sprague–Dawley rats consumed normal (CON) or high fat diets for three months. After the dietary lead in, the high fat diet group was further subdivided into high fat (HF) and high fat, leptin treated (HF-LEP) animals. HF-LEP animals were injected twice daily with leptin (5 mg/100 g body weight) for 10 days, while the CON and HF animals were injected with vehicle. Following the treatment periods, all animals were prepared for and subjected to hind limb perfusion. The high fat diet decreased rates of insulin-stimulated skeletal muscle glucose uptake and glycogen synthesis in the red gastrocnemius (RG), but did not affect glycogen synthase activity, rates of glucose oxidation or nonoxidative disposal of glucose. Of interest, IRS-1-associated PI3-K activity and total GLUT4 protein concentration were reduced in the RG of the high fat-fed animals. Leptin treatment increased rates of insulin-stimulated glucose uptake and glucose oxidation, and normalized rates of glycogen synthesis. Leptin appeared to mediate these effects by normalizing insulin-stimulated PI3-K activation and GLUT4 protein concentration in the RG. Collectively, these data suggest that chronic leptin treatment reverses the effects of a high fat diet thereby allowing the insulin signaling cascade and glucose transport effector system to be fully activated which in turn affects the amount of glucose that is transported across the plasma membrane and made available for glycogen synthesis.