ABSTRACT
Adiponectin and its receptors are inversely related to the degree of obesity and have been identified as potential therapeutic targets for the treatment of obesity. In this study, we evaluated the effect of hydrodynamic delivery of adiponectin and/or its receptor 2 (adipoR2) genes on controlling the development of obesity and insulin resistance in AKR/J mice fed a high-fat diet. An increase in adiponectin and adipoR2 gene expression by hydrodynamic gene delivery prevented diet-induced weight gain, reduced fat accumulation in liver and adipose tissue, and improved insulin sensitivity. Beneficial effects were seen with reduced gluconeogenesis in the liver and lipogenesis in the liver, white adipose tissue and skeletal muscle. Real-time PCR analysis demonstrated overexpression of adiponectin and adipoR2 significantly suppressed transcription of phosphoenolpyruvate carboxykinase (pepck), glucose-6-phosphatase (g6pase), stearoyl CoA desaturase 1 (scd-1) and fatty acid synthase (fas) gene. Inhibition effects were mediated by activating the AMP-activated protein kinase (AMPK). These results prove that elevation of adiponectin and/or adipoR2 expression via gene transfer is an effective approach in managing obesity epidemics.
Subject(s)
Adiponectin/genetics , Genetic Therapy , Obesity/genetics , Obesity/therapy , Receptors, Adiponectin/genetics , Adiponectin/administration & dosage , Animals , Diet, High-Fat , Fatty Acid Synthases/antagonists & inhibitors , Fatty Acid Synthases/metabolism , Gene Expression Regulation/drug effects , Gene Expression Regulation/genetics , Gene Transfer Techniques , Glucose-6-Phosphatase/antagonists & inhibitors , Glucose-6-Phosphatase/metabolism , Humans , Hydrodynamics , Insulin/genetics , Insulin/metabolism , Insulin Resistance/genetics , Lipid Metabolism/drug effects , Lipid Metabolism/genetics , Mice , Obesity/pathology , Phosphoenolpyruvate Carboxykinase (ATP)/antagonists & inhibitors , Phosphoenolpyruvate Carboxykinase (ATP)/metabolism , Receptors, Adiponectin/administration & dosage , Stearoyl-CoA Desaturase/antagonists & inhibitors , Stearoyl-CoA Desaturase/metabolismABSTRACT
Microvascular recruitment in muscle is a determinant of insulin sensitivity. Whether perivascular adipose tissue (PVAT) is involved in disturbed insulin-induced vasoreactivity is unknown, as are the underlying mechanisms. This study investigates whether PVAT regulates insulin-induced vasodilation in muscle, the underlying mechanisms, and how obesity disturbs this vasodilation. Insulin-induced vasoreactivity of resistance arteries was studied with PVAT from C57BL/6 or db/db mice. PVAT weight in muscle was higher in db/db mice compared with C57BL/6 mice. PVAT from C57BL/6 mice uncovered insulin-induced vasodilation; this vasodilation was abrogated with PVAT from db/db mice. Blocking adiponectin abolished the vasodilator effect of insulin in the presence of C57BL/6 PVAT, and adiponectin secretion was lower in db/db PVAT. To investigate this interaction further, resistance arteries of AMPKα2(+/+) and AMPKα2(-/-) were studied. In AMPKα2(-/-) resistance arteries, insulin caused vasoconstriction in the presence of PVAT, and AMPKα2(+/+) resistance arteries showed a neutral response. On the other hand, inhibition of the inflammatory kinase Jun NH(2)-terminal kinase (JNK) in db/db PVAT restored insulin-induced vasodilation in an adiponectin-dependent manner. In conclusion, PVAT controls insulin-induced vasoreactivity in the muscle microcirculation through secretion of adiponectin and subsequent AMPKα2 signaling. PVAT from obese mice inhibits insulin-induced vasodilation, which can be restored by inhibition of JNK.
