Muscle-Specific IRS-1 Ser->Ala Transgenic Mice Are Protected From Fat-Induced Insulin Resistance in Skeletal Muscle

Growth hormone (GH) excess is associated with insulin resistance, but the molecular mechanisms of this association are poorly understood. In the current work, we have examined the consequences of exposure to high GH levels on the early steps of the insulin-signaling system in the muscle of bovine (b) GH-transgenic mice. The protein content and the tyrosine phosphorylation state of the insulin receptor (IR), the IR substrate-1 (IRS-1), the association between IRS-1 and the p85 subunit of phosphatidylinositol (PI) 3-kinase, and the phosphotyrosine-derived PI 3-kinase activity in this tissue were studied. We found that in skeletal muscle of bGH-transgenic mice, exposure to high circulating GH levels results in 1) reduced IR abundance, 2) reduced IR tyrosine phosphorylation, 3) reduced efficiency of IRS-1 tyrosine phosphorylation, and 4) defective activation of PI 3-kinase by insulin. These alterations may be related to the insulin resistance exhibited by these animals.

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Prevention of obesity and insulin resistance by glucokinase expression in skeletal muscle of transgenic mice

The FASEB Journal ◽

10.1096/fj.03-0081fje ◽

2003 ◽

Vol 17 (14) ◽

pp. 1-16 ◽

Cited By ~ 11

Author(s):

Pedro Jose Otaegui ◽

Tura Ferre ◽

Efren Riu ◽

Fatima Bosch

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Transgenic Mice

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Transgenic mice with dominant negative PKC-theta in skeletal muscle: A new model of insulin resistance and obesity

Journal of Cellular Physiology ◽

10.1002/jcp.10278 ◽

2003 ◽

Vol 196 (1) ◽

pp. 89-97 ◽

Cited By ~ 52

Author(s):

C. Serra ◽

M. Federici ◽

A. Buongiorno ◽

M.I. Senni ◽

S. Morelli ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Transgenic Mice ◽

Dominant Negative ◽

New Model

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Increased lipid accumulation and insulin resistance in transgenic mice expressing DGAT2 in glycolytic (type II) muscle

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00158.2007 ◽

2007 ◽

Vol 293 (6) ◽

pp. E1772-E1781 ◽

Cited By ~ 59

Author(s):

Malin C. Levin ◽

Mara Monetti ◽

Matthew J. Watt ◽

Mini P. Sajan ◽

Robert D. Stevens ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Transgenic Mice ◽

Lipid Accumulation ◽

Fatty Acyl ◽

Whole Body ◽

Lipid Deposition ◽

Adult Mice ◽

Insulin Tolerance

Insulin resistance and type 2 diabetes are frequently accompanied by lipid accumulation in skeletal muscle. However, it is unknown whether primary lipid deposition in skeletal muscle is sufficient to cause insulin resistance or whether the type of muscle fiber, oxidative or glycolytic fiber, is an important determinant of lipid-mediated insulin resistance. Here we utilized transgenic mice to test the hypothesis that lipid accumulation specifically in glycolytic muscle promotes insulin resistance. Overexpression of DGAT2, which encodes an acyl-CoA:diacylglycerol acyltransferase that catalyzes triacylglycerol (TG) synthesis, in glycolytic muscle of mice increased the content of TG, ceramides, and unsaturated long-chain fatty acyl-CoAs in young adult mice. This lipid accumulation was accompanied by impaired insulin signaling and insulin-mediated glucose uptake in glycolytic muscle and impaired whole body glucose and insulin tolerance. We conclude that DGAT2-mediated lipid deposition specifically in glycolytic muscle promotes insulin resistance in this tissue and may contribute to the development of diabetes.

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Skeletal Muscle Tissue Trib3 Links Obesity with Insulin Resistance by Autophagic Degradation of AKT2

Cellular Physiology and Biochemistry ◽

10.1159/000492264 ◽

2018 ◽

Vol 48 (4) ◽

pp. 1543-1555 ◽

Cited By ~ 4

Author(s):

Minseo Kwon ◽

Ji Eom ◽

Donghwan Kim ◽

Jinhwan Kim ◽

Jose Heredia ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Glucose Metabolism ◽

Transgenic Mice ◽

Glucose Uptake ◽

Protein Turnover ◽

Physiological Role ◽

Protein Homeostasis ◽

Muscle Tissues ◽

Autophagic Degradation

Background/Aims: Obesity is a serious health risk factor strongly associated with insulin resistance and type 2 diabetes; however, the underlying mechanisms associating obesity with insulin resistance remain unknown. In this study, we explored the physiological role of Trib3 in regulating glucose metabolism in skeletal muscle tissues in a Trib3 transgenic mice model. Methods: Glucose metabolism in transgenic mice overexpressing Trib3 specifically in the skeletal muscle was examined by glucose/insulin tolerance test, metabolic cage studies, and glucose uptake assay. The effect of Trib3 overexpression on AKT phosphorylation and AKT protein turnover were assessed by RT-PCR and immunoblot analysis. Subcellular distribution of Trib3 and AKT1/2 was determined by microscopic analysis, co-immunoprecipitation experiments, and limited-detergent extraction of subcellular organelles. Ubiquitin assay was performed and ATG7 deficient cell line was employed to address the mechanisms of Trib3-dependent AKT protein homeostasis. Results: We found that Trib3 expression in skeletal muscle is elevated in obese conditions, and transgenic mice that overexpressed Trib3, specifically in skeletal muscle tissues, displayed impaired glucose homeostasis by suppressing insulin-stimulated glucose uptake. Disruption of insulin signaling in skeletal muscle Trib3 transgenic mice may occur due to the specific downregulation of AKT2 but not AKT1. Autophagy regulated AKT2 protein turnover, and Trib3 overexpression stimulated autophagic degradation of AKT2 by promoting AKT2 ubiquitination. Conclusion: Because diet-induced obesity upregulates Trib3 and downregulates AKT2 in skeletal muscle tissues, Trib3 may play a key role in establishing an association between obesity and insulin resistance by regulating AKT2 protein homeostasis.

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Activation of the Hexosamine Signaling Pathway in Adipose Tissue Results in Decreased Serum Adiponectin and Skeletal Muscle Insulin Resistance

Endocrinology ◽

10.1210/en.2003-0812 ◽

2004 ◽

Vol 145 (5) ◽

pp. 2118-2128 ◽

Cited By ~ 49

Author(s):

Mark Hazel ◽

Robert C. Cooksey ◽

Deborah Jones ◽

Glendon Parker ◽

John L. Neidigh ◽

...

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Adipose Tissue ◽

Transgenic Mice ◽

Serum Adiponectin ◽

Glucose Disposal ◽

Mrna Levels ◽

Muscle Insulin Resistance ◽

Insulin Resistant ◽

Skeletal Muscle Insulin Resistance

Abstract Overexpression of the rate-limiting enzyme for hexosamine synthesis (glutamine:fructose-6-phosphate amidotransferase) in muscle and adipose tissue of transgenic mice was previously shown to result in insulin resistance and hyperleptinemia. Explanted muscle from transgenic mice was not insulin resistant in vitro, suggesting that muscle insulin resistance could be mediated by soluble factors from fat tissue. To dissect the relative contributions of muscle and fat to hexosamine-induced insulin resistance, we overexpressed glutamine:fructose-6-phosphate amidotransferase 2.5-fold, specifically in fat under control of the aP2 promoter. Fasting glucose, insulin, and triglycerides were unchanged in the transgenic mice; leptin and β-hydroxybutyrate levels were 91% and 29% higher, respectively. Fasted transgenic mice have mild glucose intolerance and skeletal muscle insulin resistance in vivo. In fasting transgenic mice, glucose disposal rates with hyperinsulinemia were decreased 27% in females and 10% in males. Uptake of 2-deoxy-d-glucose into muscle was diminished by 45% in female and 21% in male transgenics. Serum adiponectin was also lower in the fasted transgenics, by 37% in females and 22% in males. TNFα and resistin mRNA levels in adipose tissue were not altered in the fasted transgenics; levels of mRNA for leptin were increased and peroxisome proliferator-activated receptor γ decreased. To further explore the relationship between adiponectin and insulin sensitivity, we examined mice that have been refed for 6 h after a 24-h fast. Refeeding wild-type mice resulted in decreased serum adiponectin and increased leptin. In transgenic mice, however, the regulation of these hormones by refeeding was lost for adiponectin and diminished for leptin. Refed transgenic female and male mice no longer exhibited decreased serum adiponectin in the refed state, and they were no longer insulin resistant as by lower or unchanged insulin and glucose levels. We conclude that increased hexosamine levels in fat, mimicking excess nutrient delivery, are sufficient to cause insulin resistance in skeletal muscle. Changes in serum adiponectin correlate with the insulin resistance of the transgenic animals.

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Selective activation of PPARγ in skeletal muscle induces endogenous production of adiponectin and protects mice from diet-induced insulin resistance

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.00446.2009 ◽

2010 ◽

Vol 298 (1) ◽

pp. E28-E37 ◽

Cited By ~ 69

Author(s):

Rajesh H. Amin ◽

Suresh T. Mathews ◽

Heidi S. Camp ◽

Liyun Ding ◽

Todd Leff

Keyword(s):

Insulin Resistance ◽

Skeletal Muscle ◽

Insulin Sensitivity ◽

Transgenic Mice ◽

Muscle Tissue ◽

Glucose Homeostasis ◽

Muscle Cells ◽

Whole Body ◽

Fiber Types ◽

Dependent Manner

The nuclear receptor peroxisome proliferator-activated receptor (PPAR)γ plays a key role in regulating whole body glucose homeostasis and insulin sensitivity. Although it is expressed most highly in adipose, it is also present at lower levels in many tissues, including skeletal muscle. The role muscle PPARγ plays in metabolic regulation and in mediating the antidiabetic effects of the thiazolidinediones is not understood. The goal of this work was to examine the molecular and physiological effects of PPARγ activation in muscle cells. We found that pharmacological activation of PPARγ in primary cultured myocytes, and genetic activation of muscle PPARγ in muscle tissue of transgenic mice, induced the production of adiponectin directly from muscle cells. This muscle-produced adiponectin was functional and capable of stimulating adiponectin signaling in myocytes. In addition, elevated skeletal muscle PPARγ activity in transgenic mice provided a significant protection from high-fat diet-induced insulin resistance and associated changes in muscle phenotype, including reduced myocyte lipid content and an increase in the proportion of oxidative muscle fiber types. Our findings demonstrate that PPARγ activation in skeletal muscle can have a significant protective effect on whole body glucose homeostasis and insulin resistance and that myocytes can produce and secrete functional adiponectin in a PPARγ-dependent manner. We propose that activation of PPARγ in myocytes induces a local production of adiponectin that acts on muscle tissue to improve insulin sensitivity.

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