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.

Hypophagia and metabolic adaptations in mice with defective ATGL-mediated lipolysis cause resistance to HFD-induced obesity

“…It is intriguing to note, however, that hypophagia can be turned into hyperphagia upon treatment of AKO/cTg mice with the synthetic PPAR-γ agonist rosiglitazone, suggesting a function of PPAR-γ in appetite regulation. In support of this concept, several recent studies underscored the importance of PPAR-γ in the brain for the regulation of food intake (20,21). Because AKO/cTg mice lack ATGL in the brain, it is conceivable that central ATGL deficiency impairs PPAR-γ signaling in the brain, leading to reduced food intake.…”

Neuronal Sirt1 Deficiency Increases Insulin Sensitivity in Both Brain and Peripheral Tissues

“…Metabolic Studies-We performed hyperinsulinemic euglycemic clamp studies as previously described (12). Since average BW of SINKO mice is lower than control mice, relatively heavier SINKO mice and lighter control mice that have overlapped BW were selected for clamp studies.…”

“…The IS-GDR is equal to the total GDR minus the basal glucose turnover rate. We performed other metabolic measurements as previously described (12). Immunohistochemistry studies were conducted by the UCSD histology core at Moores Cancer Center.…”

“…Western Blotting and Immunoprecipitation-We performed Western blotting and immunoprecipitation as previously described (12,54). We purchased antibodies to ␤-tubulin, SOCS3, IRS-1, and IRS-2 from Millipore (Billerica, MA).…”

Naturally improving insulin resistance with amorfrutins

“…The action of TZDs is thought to occur primarily via adipose tissue PPARγ favoring white adipose tissue expandability by promoting adipocyte differentiation, hence stimulating the mobilization of ectopic fat to white adipose depots (8,9). PPARγ in other tissues, such as macrophages and brain, also seems to contribute to the insulin-sensitizing effects of TZDs (10,11). In addition, TZDs may exert protective pancreatic and cardiovascular actions.…”