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

Abstract

In adipose, muscle, liver and macrophages, signaling by the nuclear receptor PPARγ is a determinant of insulin sensitivity and this receptor mediates the insulin–sensitizing effects of thioazolidinediones (TZDs)1-4. Since PPARγ is also expressed in neurons5, we generated mice with neuron–specific Pparγ knockout (Pparγ BKO) to determine whether neuronal PPARγ signaling contributes to either weight gain or insulin resistance. During high fat diet (HFD) feeding, food intake was reduced and energy expenditure increased in Pparγ BKO mice, resulting in reduced weight gain. When treated with the TZD rosiglitazone, Pparγ BKO mice were resistant to rosiglitazone–induced hyperphagia and weight gain and, relative to rosiglitazone–treated controls, experienced only a marginal improvement in glucose metabolism. Hyperinsulinemic euglycemic clamp studies showed that the effect of rosiglitazone treatment to increase hepatic insulin sensitivity during HFD feeding was completely abolished in Pparγ 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 PPARγ signaling to limit thermogenesis and increase food intake. Neuronal PPARγ signaling is also required for the hepatic insulin sensitizing effects of TZDs.