Depot-specific effects of the PPARγ agonist rosiglitazone on adipose tissue glucose uptake and metabolism

Abstract

We investigated mechanisms whereby peroxisome proliferator-activated receptor g (PPARg) agonism redistributes lipid from visceral (VF) toward subcutaneous fat (SF) by studying the impact of PPARg activation on VF and SF glucose uptake and metabolism, lipogenesis, and enzymes involved in triacylglycerol (TAG) synthesis. VF (retroperitoneal) and SF (inguinal) of rats treated or not for 7 days with rosiglitazone (15 mg/kg/day) were evaluated in vivo for glucose uptake and lipogenesis and in vitro for glucose metabolism, gene expression, and activities of glycerolphosphate acyltransferase (GPAT), phosphatidate phosphatase-1 (or lipin-1), and diacylglycerol acyltransferase. Rosiglitazone increased SF glucose uptake, GLUT4 mRNA, and insulin-stimulated glucose oxidation, conversion to lactate, glycogen, and the glycerol and fatty acid components of TAG. In VF, only glucose incorporation into TAG-glycerol was stimulated by rosiglitazone and less so than in SF (1.5-vs. 3-fold). mRNA levels of proteins involved in glycolysis, Krebs cycle, glycogen synthesis, and lipogenesis were markedly upregulated by rosiglitazone in SF and again less so in VF. Rosiglitazone activated TAG-glycerol synthesis in vivo (2.8-vs. 1.9-fold) and lipin activity (4.6-vs. 1.5-fold) more strongly in SF than VF, whereas GPAT activity was increased similarly in both depots. The preferential increase in glucose uptake and intracellular metabolism in SF contributes to the PPARg-mediated redistribution of TAG from VF to SF, which in turn favors global insulin sensitization. White adipose tissue (WAT) plays an important role in whole-body homeostasis by acting both as an energy reservoir and as an endocrine gland secreting several adipokines that impact major metabolic tissues, such as the liver, muscle, and brain. The importance of WAT in the maintenance of a healthy whole-body homeostasis is highlighted by the direct relationship of disturbances in WAT function (obesity and lipodystrophy) with the development of several morbidities, such as Type 2 diabetes, cancer, and atherosclerosis.Peroxisome proliferator-activated receptorg (PPARg), a nuclear receptor mainly expressed in WAT, plays a key role in regulating adipose metabolic and endocrine functions. PPARg is a master regulator of adipocyte differentiation, and its activation in vivo results in adipose tissue remodeling associated with lipid redistribution from visceral fat (VF) to subcutaneous fat (SF) (1-3). More specifically, PPARg activation in both humans and rodents is associated with an enhanced ability of SF to take up and store fatty acids, especially those derived from lipoprotein-bound triacylglycerol (TAG) through lipoprotein lipase (4). Directing fat away from VF to SF depots may constitute one mechanism whereby PPARg agonism prevents the deleterious effects of VF accumulation on the development of the metabolic syndrome and the progression to cardiovascular disease.Glucose is the major substrate metabolized in WAT. It is used not only for the synthesis of glycerol 3-phosphate, ...

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