High-fat Feeding Promotes Obesity via Insulin Receptor/PI3k-Dependent Inhibition of SF-1 VMH Neurons

SF-1-expressing neurons of the ventromedial hypothalamus (VMH) control energy homeostasis, but the role of insulin action in these cells remains undefined. We show that insulin activates PI3-kinase (PI3k) signaling in SF-1 neurons and reduces firing frequency in these cells via activation of K(ATP)-channels. These effects are abrogated in mice with insulin receptor (IR) deficiency restricted to SF-1 neurons (SF-1(ΔIR)-mice). While body weight and glucose homeostasis remain unaltered in SF-1(ΔIR)-mice under normal chow diet, they exhibit protection from diet-induced leptin resistance, weight gain, adiposity and impaired glucose tolerance. High-fat feeding activates PI3k signaling in SF-1 neurons of control mice, and this response is attenuated in the VMH of SF-1(ΔIR)-mice. Mimicking diet-induced overactivation of PI3k signaling by disruption of the PIP(3)-phosphatase PTEN leads to increased body weight and hyperphagia under normal chow diet. Collectively, our experiments reveal a critical role for HFD-induced, insulin-dependent PI3k activation in VMH neurons to control energy homeostasis.