Brain PPAR-gamma promotes obesity and is required for the insulin-sensitizing effect of thiazolidinediones

作者：Lu Min; Sarruf David A; Talukdar Saswata; Sharma Shweta; Li Pingping; Bandyopadhyay Gautam; Nalbandian Sarah; Fan WuQiang; Gayen Jiaur R; Mahata Sushil K; Webster Nicholas J; Schwartz Michael W; Olefsky Jerrold M^*

来源：Nature Medicine, 2011, 17(5): 618-U140.

DOI：10.1038/nm.2332

In adipose tissue, muscle, liver and macrophages, signaling by the nuclear receptor peroxisome proliferator-activated receptor-gamma (PPAR-gamma) is a determinant of insulin sensitivity and this receptor mediates the insulin-sensitizing effects of thiazolidinediones (TZDs)(1-4). As PPAR-gamma is also expressed in neurons(5), we generated mice with neuron-specific Pparg knockout (Pparg brain knockout (BKO)) to determine whether neuronal PPAR-gamma signaling contributes to either weight gain or insulin sensitivity. During high-fat diet (HFD) feeding, food intake was reduced and energy expenditure increased in Pparg-BKO mice compared to Pparg(f/f) mice, resulting in reduced weight gain. Pparg-BKO mice also responded better to leptin administration than Pparg(f/f) mice. When treated with the TZD rosiglitazone, Pparg-BKO mice were resistant to rosiglitazone-induced hyperphagia and weight gain and, relative to rosiglitazone-treated Pparg(f/f) mice, experienced only a marginal improvement in glucose metabolism. Hyperinsulinemic euglycemic clamp studies showed that the increase in hepatic insulin sensitivity induced by rosiglitazone treatment during HFD feeding was completely abolished in Pparg-BKO mice, an effect associated with the failure of rosiglitazone to improve liver insulin receptor signal transduction. We conclude that excess weight gain induced by HFD feeding depends in part on the effect of neuronal PPAR-g signaling to limit thermogenesis and increase food intake. Neuronal PPAR-gamma signaling is also required for the hepatic insulin sensitizing effects of TZDs.

• 出版日期2011-5