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

M Lu, DA Sarruf, S Talukdar, S Sharma, P Li… - Nature medicine, 2011 - nature.com
M Lu, DA Sarruf, S Talukdar, S Sharma, P Li, G Bandyopadhyay, S Nalbandian, WQ Fan…
Nature medicine, 2011nature.com
In adipose tissue, muscle, liver and macrophages, signaling by the nuclear receptor
peroxisome proliferator–activated receptor-γ (PPAR-γ) is a determinant of insulin sensitivity
and this receptor mediates the insulin–sensitizing effects of thiazolidinediones (TZDs),,,. As
PPAR-γ is also expressed in neurons, we generated mice with neuron-specific Pparg
knockout (Pparg brain knockout (BKO)) to determine whether neuronal PPAR-γ signaling
contributes to either weight gain or insulin sensitivity. During high-fat diet (HFD) feeding …
Abstract
In adipose tissue, muscle, liver and macrophages, signaling by the nuclear receptor peroxisome proliferator–activated receptor-γ (PPAR-γ) is a determinant of insulin sensitivity and this receptor mediates the insulin–sensitizing effects of thiazolidinediones (TZDs),,,. As PPAR-γ is also expressed in neurons, we generated mice with neuron-specific Pparg knockout (Pparg brain knockout (BKO)) to determine whether neuronal PPAR-γ 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 Ppargf/f mice, resulting in reduced weight gain. Pparg-BKO mice also responded better to leptin administration than Ppargf/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 Ppargf/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-γ signaling to limit thermogenesis and increase food intake. Neuronal PPAR-γ signaling is also required for the hepatic insulin sensitizing effects of TZDs.
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