PPARγ ablation sensitizes proopiomelanocortin neurons to leptin during high-fat feeding

Activation of central PPAR gamma promotes food intake and body weight gain; however, the identity of the neurons that express PPAR gamma and mediate the effect of this nuclear receptor on energy homeostasis is unknown. Here, we determined that selective ablation of PPAR gamma in murine proopiomelanocortin (POMC) neurons decreases peroxisome density, elevates reactive oxygen species, and induces leptin sensitivity in these neurons. Furthermore, ablation of PPAR gamma in POMC neurons preserved the interaction between mitochondria and the endoplasmic reticulum, which is dysregulated by HFD. Compared with control animals, mice lacking PPAR gamma in POMC neurons had increased energy expenditure and locomotor activity; reduced body weight, fat mass, and food intake; and improved glucose metabolism when exposed to high-fat diet (HFD). Finally, peripheral administration of either a PPAR gamma activator or inhibitor failed to affect food intake of mice with POMC-specific PPAR gamma ablation. Taken together, our data indicate that PPAR gamma mediates cellular, biological, and functional adaptations of POMC neurons to HFD, thereby regulating whole-body energy balance.