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

ABSTRACT: The peroxisome proliferator-activated receptor-? (PPAR-?) 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. PPAR-? 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. Here we report a previously unknown role for central nervous system (CNS) PPAR-? in the regulation of energy balance. We found that both acute and chronic activation of CNS PPAR-?, by either TZDs or hypothalamic overexpression of a fusion protein consisting of PPAR-? and the viral transcriptional activator VP16 (VP16-PPAR-?), led to positive energy balance in rats. Blocking the endogenous activation of CNS PPAR-? 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.

SUBMITTER: Ryan KK 

PROVIDER: S-EPMC3089657 | biostudies-literature | 2011 May

REPOSITORIES: biostudies-literature