scholarly journals SIRT3 Is Crucial for Maintaining Skeletal Muscle Insulin Action and Protects Against Severe Insulin Resistance in High-Fat–Fed Mice

Diabetes ◽  
2015 ◽  
Vol 64 (9) ◽  
pp. 3081-3092 ◽  
Author(s):  
Louise Lantier ◽  
Ashley S. Williams ◽  
Ian M. Williams ◽  
Karen K. Yang ◽  
Deanna P. Bracy ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Action ◽  
High Fat ◽  
Severe Insulin Resistance ◽  
Muscle Insulin Action

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 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.

scholarly journals Overexpression of manganese superoxide dismutase ameliorates high-fat diet-induced insulin resistance in rat skeletal muscle

2012 ◽  
Vol 303 (6) ◽  
pp. E798-E805 ◽  
Author(s):  
Michael J. Boden ◽  
Amanda E. Brandon ◽  
Jennifer D. Tid-Ang ◽  
Elaine Preston ◽  
Donna Wilks ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Superoxide Dismutase ◽  
Insulin Action ◽  
Manganese Superoxide Dismutase ◽  
Whole Body ◽  
High Fat ◽  
Muscle Insulin Resistance ◽  
Manganese Superoxide

Elevated mitochondrial reactive oxygen species have been suggested to play a causative role in some forms of muscle insulin resistance. However, the extent of their involvement in the development of diet-induced insulin resistance remains unclear. To investigate, manganese superoxide dismutase (MnSOD), a key mitochondrial-specific enzyme with antioxidant modality, was overexpressed, and the effect on in vivo muscle insulin resistance induced by a high-fat (HF) diet in rats was evaluated. Male Wistar rats were maintained on chow or HF diet. After 3 wk, in vivo electroporation (IVE) of MnSOD expression and empty vectors was undertaken in right and left tibialis cranialis (TC) muscles, respectively. After one more week, insulin action was evaluated using hyperinsulinemic euglycemic clamp, and tissues were subsequently analyzed for antioxidant enzyme capacity and markers of oxidative stress. MnSOD mRNA was overexpressed 4.5-fold, and protein levels were increased by 70%, with protein detected primarily in the mitochondrial fraction of muscle fibers. This was associated with elevated MnSOD and glutathione peroxidase activity, indicating that the overexpressed MnSOD was functionally active. The HF diet significantly reduced whole body and TC muscle insulin action, whereas overexpression of MnSOD in HF diet animals ameliorated this reduction in TC muscle glucose uptake by 50% ( P < 0.05). Decreased protein carbonylation was seen in MnSOD overexpressing TC muscle in HF-treated animals (20% vs. contralateral control leg, P < 0.05), suggesting that this effect was mediated through an altered redox state. Thus interventions causing elevation of mitochondrial antioxidant activity may offer protection against diet-induced insulin resistance in skeletal muscle.

Hormone-sensitive lipase knockout mice have increased hepatic insulin sensitivity and are protected from short-term diet-induced insulin resistance in skeletal muscle and heart

2005 ◽  
Vol 289 (1) ◽  
pp. E30-E39 ◽  
Author(s):  
So-Young Park ◽  
Hyo-Jeong Kim ◽  
Shupei Wang ◽  
Takamasa Higashimori ◽  
Jianying Dong ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Metabolism ◽  
Insulin Action ◽  
Hormone Sensitive Lipase ◽  
Wild Type ◽  
High Fat ◽  
Hormone Sensitive ◽  
Fat Feeding

Insulin resistance in skeletal muscle and heart plays a major role in the development of type 2 diabetes and diabetic heart failure and may be causally associated with altered lipid metabolism. Hormone-sensitive lipase (HSL) is a rate-determining enzyme in the hydrolysis of triglyceride in adipocytes, and HSL-deficient mice have reduced circulating fatty acids and are resistant to diet-induced obesity. To determine the metabolic role of HSL, we examined the changes in tissue-specific insulin action and glucose metabolism in vivo during hyperinsulinemic euglycemic clamps after 3 wk of high-fat or normal chow diet in awake, HSL-deficient (HSL-KO) mice. On normal diet, HSL-KO mice showed a twofold increase in hepatic insulin action but a 40% decrease in insulin-stimulated cardiac glucose uptake compared with wild-type littermates. High-fat feeding caused a similar increase in whole body fat mass in both groups of mice. Insulin-stimulated glucose uptake was reduced by 50–80% in skeletal muscle and heart of wild-type mice after high-fat feeding. In contrast, HSL-KO mice were protected from diet-induced insulin resistance in skeletal muscle and heart, and these effects were associated with reduced intramuscular triglyceride and fatty acyl-CoA levels in the fat-fed HSL-KO mice. Overall, these findings demonstrate the important role of HSL on skeletal muscle, heart, and liver glucose metabolism.

36-OR: Energy Stress Restores Muscle Insulin Action in High-Fat (HF)-Fed SIRT3 KO Mice

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 36-OR
Author(s):  
LOUISE LANTIER ◽  
CURTIS C. HUGHEY ◽  
DAVID WASSERMAN
Keyword(s):  
Insulin Action ◽  
High Fat ◽  
Energy Stress ◽  
Muscle Insulin Action

Insulin action and resistance in obesity and noninsulin-dependent type II diabetes mellitus

1982 ◽  
Vol 243 (1) ◽  
pp. E15-E30 ◽  
Author(s):  
J. M. Olefsky ◽  
O. G. Kolterman ◽  
J. A. Scarlett
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Insulin Receptor ◽  
Insulin Action ◽  
Insulin Receptors ◽  
Tissue Level ◽  
Dependent Diabetes Mellitus ◽  
Target Tissue ◽  
Severe Insulin Resistance ◽  
Glucose Clamp Technique

Resistance to the action of insulin can result from a variety of causes, including the formation of abnormal insulin or proinsulin molecules, the presence of circulating antagonists to insulin or the insulin receptor, or defects in insulin action at the target tissue level. Defects of the latter type are characteristic of obesity and of noninsulin-dependent diabetes mellitus. Analysis of the nature of the insulin resistance in those disorders has been investigated in intact subjects with the use of the euglycemic glucose clamp technique, and both insulin receptors and insulin-mediated glucose metabolism have been studied in adipocytes and monocytes from affected individuals. In both conditions, the cause of insulin resistance is heterogeneous. In some, insulin resistance appears to be due to a defect in the insulin receptor, whereas others have a defect both in the receptor and at the postreceptor level. In both groups, more severe insulin resistance is due to the postreceptor lesion and is correctable with appropriate therapy.

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