Al-Qassab, Hind;
Smith, Mark A;
Irvine, Elaine E;
Guillermet-Guibert, Julie;
Claret, Marc;
Choudhury, Agharul I;
Selman, Colin;
... Withers, Dominic J; + view all
(2009)
Dominant Role of the p110β Isoform of PI3K over p110α in Energy Homeostasis Regulation by POMC and AgRP Neurons.
Cell Metabolism
, 10
(5)
pp. 343-354.
10.1016/j.cmet.2009.09.008.
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Abstract
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 p110α or p110β PI3K catalytic subunits in these neurons and demonstrate a dominant role for the latter in energy homeostasis regulation. In POMC neurons, p110β inactivation prevented insulin- and leptin-stimulated electrophysiological responses. POMCp110β null mice exhibited central leptin resistance, increased adiposity, and diet-induced obesity. In contrast, the response to leptin was not blocked in p110α-deficient POMC neurons. Accordingly, POMCp110α null mice displayed minimal energy homeostasis abnormalities. Similarly, in AgRP neurons, p110β had a more important role than p110α. AgRPp110α null mice displayed normal energy homeostasis regulation, whereas AgRPp110β null mice were lean, with increased leptin sensitivity and resistance to diet-induced obesity. These results demonstrate distinct metabolic roles for the p110α and p110β isoforms of PI3K in hypothalamic energy regulation.
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