Increased leptin signaling drives the response of hypothalamic LepRb neurons to diet-induced obesity.

The failure of hyperleptinemia to decrease adiposity in common forms of obesity has led to the notion that impaired leptin receptor (LepRb) signaling ("leptin resistance") might cause obesity. Because LepRb transcriptional signaling plays a central role in leptin action, we defined the control of gene expression in hypothalamic LepRb neurons in diet-induced obese (DIO) mice and in response to changes in circulating leptin. We found that LepRb neurons from DIO mice exhibited transcriptional changes similar to those induced by exogenous leptin. We also examined electrical activity in LepRb neurons from DIO mice, focusing on LepRb neurons in the ventromedial hypothalamic nucleus (VMN). This analysis revealed larger membrane depolarizations in response to current injection for VMN LepRb neurons from DIO mice. This effect was recapitulated by hyperleptinemia in vivo or exposure to elevated leptin ex vivo. Hence, hypothalamic LepRb neurons exhibit increased cellular leptin responses due to hyperleptinemia in DIO animals. These findings contradict the notion that impaired cellular leptin action underlies the development of DIO but rather suggest that increased leptin action drives DIO-associated changes in hypothalamic LepRb neuron function.