scholarly journals Effects of a brief high-fat diet and acute exercise on the mTORC1 and IKK/NF-κB pathways in rat skeletal muscle

2015 ◽  
Vol 40 (3) ◽  
pp. 251-262 ◽  
Author(s):  
Carlos M. Castorena ◽  
Edward B. Arias ◽  
Naveen Sharma ◽  
Gregory D. Cartee
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Uptake ◽  
High Fat Diet ◽  
Acute Exercise ◽  
Exercise Session ◽  
High Fat ◽  
Insulin Resistant ◽  
Mtorc1 Pathway ◽  
Exercise Induced

One exercise session can improve subsequent insulin-stimulated glucose uptake by skeletal muscle in healthy and insulin-resistant individuals. Our first aim was to determine whether a brief (2 weeks) high-fat diet (HFD) that caused muscle insulin resistance would activate the mammalian target of rapamycin complex 1 (mTORC1) and/or inhibitor of κB kinase/nuclear factor κB (IKK/NF-κB) pathways, which are potentially linked to induction of insulin resistance. Our second aim was to determine whether acute exercise that improved insulin-stimulated glucose uptake by muscles would attenuate activation of these pathways. We compared HFD-fed rats with rats fed a low-fat diet (LFD). Some animals from each diet group were sedentary and others were studied 3 h postexercise, when insulin-stimulated glucose uptake was increased. The results did not provide evidence that brief HFD activated either the mTORC1 (including phosphorylation of mTORSer2448, TSC2Ser939, p70S6KThr412, and RPS6Ser235/236) or the IKK/NF-κB (including abundance of IκBα or phosphorylation of NF-κBSer536, IKKα/βSer177/181, and IκBSer32) pathway in insulin-resistant muscles. Exercise did not oppose the activation of either pathway, as evidenced by no attenuation of phosphorylation of key proteins in the IKK/NF-κB pathway (NF-κBSer536, IKKα/βSer177/181, and IκBSer32), unaltered IκBα abundance, and no attenuation of phosphorylation of key proteins in the mTORC1 pathway (mTORSer2448, TSC2Ser939, and RPS6Ser235/236). Instead, exercise induced greater phosphorylation of 2 proteins of the mTORC1 pathway (PRAS40Thr246 and p70S6KThr412) in insulin-stimulated muscles, regardless of diet. Insulin resistance induced by a brief HFD was not attributable to greater activation of the mTORC1 or the IKK/NF-κB pathway in muscle, and exercise-induced improvement in insulin sensitivity was not attributable to attenuated activation of these pathways in muscle.

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.

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.

scholarly journals Skeletal muscle fiber type-selective effects of acute exercise on insulin-stimulated glucose uptake in insulin-resistant, high-fat-fed rats

2019 ◽  
Vol 316 (5) ◽  
pp. E695-E706 ◽  
Author(s):  
Mark W. Pataky ◽  
Carmen S. Yu ◽  
Yilin Nie ◽  
Edward B. Arias ◽  
Manak Singh ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Acute Exercise ◽  
Fiber Type ◽  
Single Fiber ◽  
Male Rats ◽  
Type I ◽  
Fiber Types ◽  
High Fat ◽  
Insulin Resistant

Insulin-stimulated glucose uptake (GU) by skeletal muscle is enhanced several hours after acute exercise in rats with normal or reduced insulin sensitivity. Skeletal muscle is composed of multiple fiber types, but exercise’s effect on fiber type-specific insulin-stimulated GU in insulin-resistant muscle was previously unknown. Male rats were fed a high-fat diet (HFD; 2 wk) and were either sedentary (SED) or exercised (2-h exercise). Other, low-fat diet-fed (LFD) rats remained SED. Rats were studied immediately postexercise (IPEX) or 3 h postexercise (3hPEX). Epitrochlearis muscles from IPEX rats were incubated in 2-deoxy-[3H]glucose (2-[3H]DG) without insulin. Epitrochlearis muscles from 3hPEX rats were incubated with 2-[3H]DG ± 100 µU/ml insulin. After single fiber isolation, GU and fiber type were determined. Glycogen and lipid droplets (LDs) were assessed histochemically. GLUT4 abundance was determined by immunoblotting. In HFD-SED vs. LFD-SED rats, insulin-stimulated GU was decreased in type IIB, IIX, IIAX, and IIBX fibers. Insulin-independent GU IPEX was increased and glycogen content was decreased in all fiber types (types I, IIA, IIB, IIX, IIAX, and IIBX). Exercise by HFD-fed rats enhanced insulin-stimulated GU in all fiber types except type I. Single fiber analyses enabled discovery of striking fiber type-specific differences in HFD and exercise effects on insulin-stimulated GU. The fiber type-specific differences in insulin-stimulated GU postexercise in insulin-resistant muscle were not attributable to a lack of fiber recruitment, as indirectly evidenced by insulin-independent GU and glycogen IPEX, differences in multiple LD indexes, or altered GLUT4 abundance, implicating fiber type-selective differences in the cellular processes responsible for postexercise enhancement of insulin-mediated GLUT4 translocation.

scholarly journals Melatonin Improves Glucose Homeostasis and Endothelial Vascular Function in High-Fat Diet-Fed Insulin-Resistant Mice

Endocrinology ◽  
2009 ◽  
Vol 150 (12) ◽  
pp. 5311-5317 ◽  
Author(s):  
Claudio Sartori ◽  
Pierre Dessen ◽  
Caroline Mathieu ◽  
Anita Monney ◽  
Jonathan Bloch ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Signal Transduction ◽  
Glucose Tolerance ◽  
Glucose Homeostasis ◽  
High Fat Diet ◽  
High Fat ◽  
Insulin Resistant ◽  
Normal Chow ◽  
Underlying Mechanisms

Abstract Obesity and insulin resistance represent a problem of utmost clinical significance worldwide. Insulin-resistant states are characterized by the inability of insulin to induce proper signal transduction leading to defective glucose uptake in skeletal muscle tissue and impaired insulin-induced vasodilation. In various pathophysiological models, melatonin interacts with crucial molecules of the insulin signaling pathway, but its effects on glucose homeostasis are not known. In a diet-induced mouse model of insulin resistance and normal chow-fed control mice, we sought to assess the effects of an 8-wk oral treatment with melatonin on insulin and glucose tolerance and to understand underlying mechanisms. In high-fat diet-fed mice, but not in normal chow-fed control mice, melatonin significantly improved insulin sensitivity and glucose tolerance, as evidenced by a higher rate of glucose infusion to maintain euglycemia during hyperinsulinemic clamp studies and an attenuated hyperglycemic response to an ip glucose challenge. Regarding underlying mechanisms, we found that melatonin restored insulin-induced vasodilation to skeletal muscle, a major site of glucose utilization. This was due, at least in part, to the improvement of insulin signal transduction in the vasculature, as evidenced by increased insulin-induced phosphorylation of Akt and endoethelial nitric oxide synthase in aortas harvested from melatonin-treated high-fat diet-fed mice. In contrast, melatonin had no effect on the ability of insulin to promote glucose uptake in skeletal muscle tissue in vitro. These data demonstrate for the first time that in a diet-induced rodent model of insulin resistance, melatonin improves glucose homeostasis by restoring the vascular action of insulin.

scholarly journals Mechanisms for greater insulin-stimulated glucose uptake in normal and insulin-resistant skeletal muscle after acute exercise

2015 ◽  
Vol 309 (12) ◽  
pp. E949-E959 ◽  
Author(s):  
Gregory D. Cartee
Keyword(s):  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Glucose Uptake ◽  
Acute Exercise ◽  
Insulin Dose ◽  
Whole Body ◽  
Exercise Session ◽  
End Effector ◽  
Insulin Resistant ◽  
Normal Individuals

Enhanced skeletal muscle and whole body insulin sensitivity can persist for up to 24–48 h after one exercise session. This review focuses on potential mechanisms for greater postexercise and insulin-stimulated glucose uptake (ISGU) by muscle in individuals with normal or reduced insulin sensitivity. A model is proposed for the processes underlying this improvement; i.e., triggers initiate events that activate subsequent memory elements, which store information that is relayed to mediators, which translate memory into action by controlling an end effector that directly executes increased insulin-stimulated glucose transport. Several candidates are potential triggers or memory elements, but none have been conclusively verified. Regarding potential mediators in both normal and insulin-resistant individuals, elevated postexercise ISGU with a physiological insulin dose coincides with greater Akt substrate of 160 kDa (AS160) phosphorylation without improved proximal insulin signaling at steps from insulin receptor binding to Akt activity. Causality remains to be established between greater AS160 phosphorylation and improved ISGU. The end effector for normal individuals is increased GLUT4 translocation, but this remains untested for insulin-resistant individuals postexercise. Following exercise, insulin-resistant individuals can attain ISGU values similar to nonexercising healthy controls, but after a comparable exercise protocol performed by both groups, ISGU for the insulin-resistant group has been consistently reported to be below postexercise values for the healthy group. Further research is required to fully understand the mechanisms underlying the improved postexercise ISGU in individuals with normal or subnormal insulin sensitivity and to explain the disparity between these groups after similar exercise.

Abstract 17649: Inhibition of Src Homology 2 Domain-containing Phosphatase 1 (SHP-1) Increases Insulin Sensitivity in High-fat Diet-induced Insulin Resistant C57black6 Mice

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Janine Krüger ◽  
Markus Dagnell ◽  
Philipp Stawowy ◽  
Evren Caglayan ◽  
Arne Östman ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Body Weight ◽  
Glucose Tolerance ◽  
High Fat Diet ◽  
Metabolic Diseases ◽  
High Fat ◽  
Insulin Resistant ◽  
Cardiovascular Morbidity And Mortality

Background: Insulin resistance plays a crucial role in the development of type 2 diabetes, and exerts great impact on vascular inflammation and remodeling. At the molecular level a post-insulin receptor (IR) defect in insulin signaling has been suggested to contribute to insulin resistance. IR signaling is antagonized and tightly controlled by protein tyrosine phosphatases (PTPs). The precise role of PTPs in insulin resistance, however, has not been explored. Results: Male C57BL/6J mice were fed a high-fat diet (HFD, 60% kcal from fat) to induce insulin resistance, or a low-fat diet (LFD, 10% kcal from fat) for 10 weeks. Afterwards, HFD mice were treated with PTP-inhibitors for additional 6 weeks. Mice under HFD exhibited a significant increase in body weight as well as decreased respiratory quotient and adiponectin levels, and were characterized by impaired insulin- and glucose tolerance. Organ-based gene expression analyses in insulin-resistant mice demonstrated upregulation of SHP-1, PTP1B, LAR, and DEP-1 in insulin-sensitive organs. SHP-1 was further explored in vitro. Insulin stimulation in murine liver cells induced site-selective hyper-phosphorylation at IR tyrosine-sites Y1158, and Y1361 after inhibition of SHP-1. Furthermore, SHP-1 impairment time-dependently enhanced insulin-induced Akt- and Erk-phosphorylation, and resulted in elevated glucose uptake in skeletal muscle cells. Administration of a SHP-1 inhibitor (Sodium Stibogluconate) and a brought pan-PTP inhibitor (BMOV) in HFD mice led to improvement of both insulin- and glucose tolerance. In accordance, PTP-activity was significantly impaired in epididymal fat, skeletal muscle, and liver under BMOV treatment, being confirmed by reduced ex vivo dephosphorylation of a radioactive labelled peptide (AEEEIYGEFEAKKKK). Finally, BMOV- and SHP-1 treatment also resulted in reduced body weight. Conclusions: IR-antagonizing PTPs were organ-specifically regulated in insulin resistance. The results indicate a central role of PTPs and, in particular, of SHP-1 as endogenous antagonists of the IR. Taken together targeting PTPs led to beneficial effects in insulin resistance, and may thus improve metabolic diseases as well as cardiovascular morbidity and mortality.

Limitations to basal and insulin-stimulated skeletal muscle glucose uptake in the high-fat-fed rat

2000 ◽  
Vol 279 (5) ◽  
pp. E1064-E1071 ◽  
Author(s):  
Amy E. Halseth ◽  
Deanna P. Bracy ◽  
David H. Wasserman
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Steady State ◽  
Glucose Uptake ◽  
Glucose Concentration ◽  
High Fat Diet ◽  
High Fat ◽  
Skeletal Muscle Glucose Uptake ◽  
Fast Twitch ◽  
Total Muscle

Rats fed a high-fat diet display blunted insulin-stimulated skeletal muscle glucose uptake. It is not clear whether this is due solely to a defect in glucose transport, or if glucose delivery and phosphorylation are also impaired. To determine this, rats were fed standard chow (control rats) or a high-fat diet (HF rats) for 4 wk. Experiments were then performed on conscious rats under basal conditions or during hyperinsulinemic euglycemic clamps. Rats received primed constant infusions of 3- O-methyl-[3H]glucose (3- O-MG) and [1-14C]mannitol. Total muscle glucose concentration and the steady-state ratio of intracellular to extracellular 3- O-MG concentration [which distributes based on the transsarcolemmal glucose gradient (TSGG)] were used to calculate glucose concentrations at the inner and outer sarcolemmal surfaces ([G]imand [G]om, respectively) in soleus. Total muscle glucose was also measured in two fast-twitch muscles. Muscle glucose uptake was markedly decreased in HF rats. In control rats, hyperinsulinemia resulted in a decrease in soleus TSGG compared with basal, due to increased [G]im. In HF rats during hyperinsulinemia, [G]imalso exceeded zero. Hyperinsulinemia also decreased muscle glucose in HF rats, implicating impaired glucose delivery. In conclusion, defects in extracellular and intracellular components of muscle glucose uptake are of major functional significance in this model of insulin resistance.

scholarly journals Tofogliflozin Improves Insulin Resistance in Skeletal Muscle and Accelerates Lipolysis in Adipose Tissue in Male Mice

Endocrinology ◽  
2015 ◽  
Vol 157 (3) ◽  
pp. 1029-1042 ◽  
Author(s):  
Atsushi Obata ◽  
Naoto Kubota ◽  
Tetsuya Kubota ◽  
Masahiko Iwamoto ◽  
Hiroyuki Sato ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Adipose Tissue ◽  
Glucose Uptake ◽  
White Adipose Tissue ◽  
High Fat Diet ◽  
Molecular Mechanisms ◽  
The Body ◽  
High Fat ◽  
Ad Libitum

Abstract Sodium glucose cotransporter 2 inhibitors have attracted attention as they exert antidiabetic and antiobesity effects. In this study, we investigated the effects of tofogliflozin on glucose homeostasis and its metabolic consequences and clarified the underlying molecular mechanisms. C57BL/6 mice were fed normal chow containing tofogliflozin (0.005%) for 20 weeks or a high-fat diet containing tofogliflozin (0.005%) for 8 weeks ad libitum. In addition, the animals were pair-fed in relation to controls to exclude the influence of increased food intake. Tofogliflozin reduced the body weight gain, mainly because of fat mass reduction associated with a diminished adipocyte size. Glucose tolerance and insulin sensitivity were ameliorated. The serum levels of nonesterified fatty acid and ketone bodies were increased and the respiratory quotient was decreased in the tofogliflozin-treated mice, suggesting the acceleration of lipolysis in the white adipose tissue and hepatic β-oxidation. In fact, the phosphorylation of hormone-sensitive lipase and the adipose triglyceride lipase protein levels in the white adipose tissue as well as the gene expressions related to β-oxidation, such as Cpt1α in the liver, were significantly increased. The hepatic triglyceride contents and the expression levels of lipogenic genes were decreased. Pair-fed mice exhibited almost the same results as mice fed an high-fat diet ad libitum. Moreover, a hyperinsulinemic-euglycemic clamp revealed that tofogliflozin improved insulin resistance by increasing glucose uptake, especially in the skeletal muscle, in pair-fed mice. Taken together, these results suggest tofogliflozin ameliorates insulin resistance and obesity by increasing glucose uptake in skeletal muscle and lipolysis in adipose tissue.

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