A role for central nervous system PPAR-γ in the regulation of energy balance

The peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a nuclear receptor that is activated by lipids to induce the expression of genes involved in lipid and glucose metabolism, thereby converting nutritional signals into metabolic consequences(1). PPAR-gamma is the target of the thiazolidinedione (TZD) class of insulin-sensitizing drugs, which have been widely prescribed to treat type 2 diabetes mellitus. A common side effect of treatment with TZDs is weight gain(2). Here we report a previously unknown role for central nervous system (CNS) PPAR-gamma in the regulation of energy balance. We found that both acute and chronic activation of CNS PPAR-gamma, by either TZDs or hypothalamic overexpression of a fusion protein consisting of PPAR-gamma and the viral transcriptional activator VP16 (VP16-PPAR-gamma), led to positive energy balance in rats. Blocking the endogenous activation of CNS PPAR-gamma with pharmacological antagonists or reducing its expression with shRNA led to negative energy balance, restored leptin sensitivity in high-fat-diet (HFD)-fed rats and blocked the hyperphagic response to oral TZD treatment. These findings have implications for the widespread clinical use of TZD drugs and for understanding the etiology of diet-induced obesity.