Effects of pioglitazone on adipose tissue remodeling within the setting ofobesity and insulin resistance

Obesity and dysfunctional energy partitioning can lead to the development o f insulin resistance and type 2 diabetes. The antidiabetic thiazolidinedion es shift the energy balance toward storage, leading to an increase in whole -body adiposity. These studies examine the effects of pioglitazone (Pio) on adipose tissue physiology, accumulation, and distribution in female Zucker fa/fa) rats. Pio treatment (up to 28 days) decreased the insulin-resistant and hyperlipidemic states and increased food consumption and whole-body ad iposity. Magnetic resonance imaging (MRI) analysis and weights of fat pads demonstrated that the increase in adiposity was not only limited to the maj or fat depots but also to fat deposition throughout the body. Adipocyte siz ing profiles, fat pad histology, and DNA content show that Pio treatment in creased the number of small adipocytes because of both the appearance of ne w adipocytes and the shrinkage and/or disappearance of existing mature adip ocytes. The remodeling was time dependent, with new small adipocytes appear ing in clusters throughout the fat pad, and accompanied by a three- to four fold increase in citrate synthase and fatty acid synthase activity. The app earance of new fat cells and the increase in fat mass were depot specific, with a rank order of responsiveness of ovarian > retroperitoneal > subcutan eous. This differential depot effect resulted in a redistribution of the fa t mass in the abdominal region such that there was an increase in the visce ral:subcutaneous ratio, as confirmed by MRI analysis. Although the increase d adiposity is paradoxical to an improvement in insulin sensitivity, the qu antitative increase of adipose mass should be viewed in context of the qual itative changes in adipose tissue, including the remodeling of adipocytes t o a smaller size with higher lipid storage potential. This shift in energy balance is likely to result in lower circulating free fatty acid levels, ul timately improving insulin sensitivity and the metabolic state.