Steroidogenic factor 1 (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 phosphatidylinositol-3-OH kinase (PI3K) signaling in SF-1 neurons and reduces firing frequency in these cells through activation of K ATP channels. These effects were abrogated in mice with insulin receptor deficiency restricted to SF-1 neurons (SF-1 Î "IR mice). Whereas body weight and glucose homeostasis remained the same in SF-1 Î "IR mice as in controls under a normal chow diet, they were protected from diet-induced leptin resistance, weight gain, adiposity and impaired glucose tolerance. High-fat feeding activated PI3K signaling in SF-1 neurons of control mice, and this response was attenuated in the VMH of SF-1 Î "IR mice. Mimicking diet-induced overactivation of PI3K signaling by disruption of the phosphatidylinositol-3,4, 5-trisphosphate phosphatase PTEN led to increased body weight and hyperphagia under a normal chow diet. Collectively, our experiments reveal that high-fat diet-"induced, insulin-dependent PI3K activation in VMH neurons contributes to obesity development.
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