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

2003 ◽  
Vol 196 (1) ◽  
pp. 89-97 ◽  
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

scholarly journals NF-κB-Inducing Kinase (NIK) Mediates Skeletal Muscle Insulin Resistance: Blockade by Adiponectin

Endocrinology ◽  
2011 ◽  
Vol 152 (10) ◽  
pp. 3622-3627 ◽  
Author(s):  
Sanjeev Choudhary ◽  
Sandeep Sinha ◽  
Yanhua Zhao ◽  
Srijita Banerjee ◽  
Padma Sathyanarayana ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Glucose Uptake ◽  
Kinase Activity ◽  
Pi3 Kinase ◽  
Dominant Negative ◽  
Muscle Insulin Resistance ◽  
Akt Phosphorylation ◽  
Skeletal Muscle Insulin Resistance ◽  
Obese Subjects

Enhanced levels of nuclear factor (NF)-κB-inducing kinase (NIK), an upstream kinase in the NF-κB pathway, have been implicated in the pathogenesis of chronic inflammation in diabetes. We investigated whether increased levels of NIK could induce skeletal muscle insulin resistance. Six obese subjects with metabolic syndrome underwent skeletal muscle biopsies before and six months after gastric bypass surgery to quantitate NIK protein levels. L6 skeletal myotubes, transfected with NIK wild-type or NIK kinase-dead dominant negative plasmids, were treated with insulin alone or with adiponectin and insulin. Effects of NIK overexpression on insulin-stimulated glucose uptake were estimated using tritiated 2-deoxyglucose uptake. NF-κB activation (EMSA), phosphatidylinositol 3 (PI3) kinase activity, and phosphorylation of inhibitor κB kinase β and serine-threonine kinase (Akt) were measured. After weight loss, skeletal muscle NIK protein was significantly reduced in association with increased plasma adiponectin and enhanced AMP kinase phosphorylation and insulin sensitivity in obese subjects. Enhanced NIK expression in cultured L6 myotubes induced a dose-dependent decrease in insulin-stimulated glucose uptake. The decrease in insulin-stimulated glucose uptake was associated with a significant decrease in PI3 kinase activity and protein kinase B/Akt phosphorylation. Overexpression of NIK kinase-dead dominant negative did not affect insulin-stimulated glucose uptake. Adiponectin treatment inhibited NIK-induced NF-κB activation and restored insulin sensitivity by restoring PI3 kinase activation and subsequent Akt phosphorylation. These results indicate that NIK induces insulin resistance and further indicate that adiponectin exerts its insulin-sensitizing effect by suppressing NIK-induced skeletal muscle inflammation. These observations suggest that NIK could be an important therapeutic target for the treatment of insulin resistance associated with inflammation in obesity and type 2 diabetes.

scholarly journals Adiponectin improves insulin sensitivity via activation of autophagic flux

2017 ◽  
Vol 59 (4) ◽  
pp. 339-350 ◽  
Author(s):  
Penny Ahlstrom ◽  
Esther Rai ◽  
Suharto Chakma ◽  
Hee Ho Cho ◽  
Palanivel Rengasamy ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Insulin Sensitivity ◽  
Er Stress ◽  
Western Blotting ◽  
Muscle Cells ◽  
Dominant Negative ◽  
Skeletal Muscle Cells ◽  
Dominant Negative Mutant ◽  
Autophagic Flux

Skeletal muscle insulin resistance is known to play an important role in the pathogenesis of diabetes, and one potential causative cellular mechanism is endoplasmic reticulum (ER) stress. Adiponectin mediates anti-diabetic effects via direct metabolic actions and by improving insulin sensitivity, and we recently demonstrated an important role in stimulation of autophagy by adiponectin. However, there is limited knowledge on crosstalk between autophagy and ER stress in skeletal muscle and in particular how they are regulated by adiponectin. Here, we utilized the model of high insulin/glucose (HIHG)-induced insulin resistance, determined by measuring Akt phosphorylation (T308 and S473) and glucose uptake in L6 skeletal muscle cells. HIHG reduced autophagic flux measured by LC3 and p62 Western blotting and tandem fluorescent RFP/GFP-LC3 immunofluorescence (IF). HIHG also induced ER stress assessed by thioflavin T/KDEL IF, pIRE1, pPERK, peIF2α and ATF6 Western blotting and induction of a GRP78-mCherry reporter. Induction of autophagy by adiponectin or rapamycin attenuated HIHG-induced ER stress and improved insulin sensitivity. The functional significance of enhanced autophagy was validated by demonstrating a lack of improved insulin sensitivity in response to adiponectin in autophagy-deficient cells generated by overexpression of dominant negative mutant of Atg5. In summary, adiponectin-induced autophagy in skeletal muscle cells alleviated HIHG-induced ER stress and insulin resistance.

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

Diabetes ◽  
2008 ◽  
Vol 57 (10) ◽  
pp. 2644-2651 ◽  
Author(s):  
K. Morino ◽  
S. Neschen ◽  
S. Bilz ◽  
S. Sono ◽  
D. Tsirigotis ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Transgenic Mice

MKR mice are resistant to the metabolic actions of both insulin and adiponectin: discordance between insulin resistance and adiponectin responsiveness

2006 ◽  
Vol 291 (2) ◽  
pp. E298-E305 ◽  
Author(s):  
Chul-Hee Kim ◽  
Patricia Pennisi ◽  
Hong Zhao ◽  
Shoshana Yakar ◽  
Jeanne B. Kaufman ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Hepatic Glucose Production ◽  
Glucose Production ◽  
Dominant Negative ◽  
Metabolic Phenotype ◽  
Dominant Negative Mutant ◽  
Acid Oxidation ◽  
Mrna Levels ◽  
Normal Expression

Most rodent models of insulin resistance are accompanied by decreased circulating adiponectin levels. Adiponectin treatment improves the metabolic phenotype by increasing fatty acid oxidation in skeletal muscle and suppressing hepatic glucose production. Muscle IGF-I receptor (IGF-IR)-lysine-arginine (MKR) mice expressing dominant-negative mutant IGF-IRs in skeletal muscle are diabetic with insulin resistance in muscle, liver, and adipose tissue. Adiponectin levels are elevated in MKR mice, suggesting an unusual discordance between insulin resistance and adiponectin responsiveness. Therefore, we investigated the metabolic actions of adiponectin in MKR mice. MKR and ob/ob mice were treated both acutely (28 μg/g) and chronically (for 2 wk) with full-length adiponectin. Acute hypoglycemic effects of adiponectin were evident only in ob/ob mice but not in MKR mice. Chronic adiponectin treatment significantly improved both insulin sensitivity and glucose tolerance in ob/ob but not in MKR mice. Adiponectin receptor mRNA levels and adiponectin-stimulated phosphorylation of AMPK in skeletal muscle and liver were similar among MKR, wild-type, and ob/ob mice. Thus MKR mice are adiponectin resistant despite normal expression of adiponectin receptors and normal AMPK phosphorylation in muscle and liver. MKR mice may be a useful model for dissecting relationships between insulin resistance and adiponectin action in regulation of glucose homeostasis.

Alterations in the early steps of the insulin-signaling system in skeletal muscle of GH-transgenic mice

1999 ◽  
Vol 277 (3) ◽  
pp. E447-E454 ◽  
Author(s):  
Fernando P. Dominici ◽  
Debora Cifone ◽  
Andrzej Bartke ◽  
Daniel Turyn
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Transgenic Mice ◽  
Tyrosine Phosphorylation ◽  
Insulin Signaling ◽  
Molecular Mechanisms ◽  
Kinase Activity ◽  
Signaling System ◽  
Phosphorylation State ◽  
Gh Excess

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.

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

2003 ◽  
Vol 17 (14) ◽  
pp. 1-16 ◽  
Author(s):  
Pedro Jose Otaegui ◽  
Tura Ferre ◽  
Efren Riu ◽  
Fatima Bosch
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
Transgenic Mice

scholarly journals Insulin resistance in skeletal muscle of the male Otsuka Long-Evans Tokushima Fatty rat, a new model of NIDDM

Diabetologia ◽  
1995 ◽  
Vol 38 (9) ◽  
pp. 1033-1041 ◽  
Author(s):  
T. Sato ◽  
Y. Asahi ◽  
K. Toide ◽  
N. Nakayama
Keyword(s):  
Insulin Resistance ◽  
Skeletal Muscle ◽  
New Model ◽  
Long Evans

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

2007 ◽  
Vol 293 (6) ◽  
pp. E1772-E1781 ◽  
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.

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.

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