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 KATP-channels. These effects are abrogated in mice with insulin receptor (IR) deficiency restricted to SF-1 neurons (SF-1ΔIR-mice). While body weight and glucose homeostasis remain unaltered in SF-1ΔIR-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-1ΔIR-mice. Mimicking diet-induced overactivation of PI3k signaling by disruption of the PIP3-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.

Leptin-stimulated Stat3 activation in proopiomelanocortin (POMC)-expressing neurons of the hypothalamus plays an important role in

Insulin- and leptin-stimulated phosphatidylinositol-3 kinase (PI3K) activation has been demonstrated to play a critical role in central control of energy homeostasis. To delineate the importance of pathways downstream of PI3K specifically in pro-opiomelanocortin (POMC) cell regulation, we have generated mice with selective inactivation of 3-phosphoinositide-dependent protein kinase 1 (PDK1) in POMC-expressing cells (PDK1(DeltaPOMC) mice). PDK1(DeltaPOMC) mice initially display hyperphagia, increased body weight, and impaired glucose metabolism caused by reduced hypothalamic POMC expression. On the other hand, PDK1(DeltaPOMC) mice exhibit progressive, severe hypocortisolism caused by loss of POMC-expressing corticotrophs in the pituitary. Expression of a dominant-negative mutant of FOXO1 specifically in POMC cells is sufficient to ameliorate positive energy balance in PDK1(DeltaPOMC) mice but cannot restore regular pituitary function. These results reveal important but differential roles for PDK1 signaling in hypothalamic and pituitary POMC cells in the control of energy homeostasis and stress response.