Dominant Role of the p110 beta Isoform of PI3K over p110 alpha in Energy Homeostasis Regulation by POMC and AgRP Neurons

PI3K signaling is thought to mediate leptin and insulin action in hypothalamic pro-opiomelanocortin (POMC) and agouti-related protein (AgRP) neurons, key regulators of energy homeostasis, through largely unknown mechanisms. We inactivated either p110 alpha or p110 beta PI3K catalytic subunits in these neurons and demonstrate a dominant role for the latter in energy homeostasis; regulation. In POMC neurons, p110 beta inactivation prevented insulin- and leptin-stimulated electrophysiological responses. POMCp110 beta null mice exhibited central leptin resistance, increased adiposity, and diet-induced obesity. In contrast, the response to leptin was not blocked in p110 alpha-deficient POMC neurons. Accordingly, POMCp110 alpha null mice displayed minimal energy homeostasis abnormalities. Similarly, in AgRP neurons, p110 beta had a more important role than p110 alpha. AgRPp110 alpha null mice displayed normal energy homeostasis regulation, whereas AgRPp110 beta null mice were lean, with increased leptin sensitivity and resistance to diet-induced obesity. These results demonstrate distinct metabolic roles for the p110 alpha and p110 beta isoforms; of PI3K in hypothalamic energy regulation.