Dominant role of the p110β isoform of PI3K over p110alpha in energy homeostasis regulation by POMC and AgRP neurons

Hind Al-Qassab, Mark A Smith, Elaine E Irvine, Julie Guillermet-Guibert, Marc Claret, Agharul I Choudhury, Colin Selman, Kaisa Piipari, Melanie Clements, Steven Lingard, Keval Chandarana, Jimmy D Bell, Gregory S Barsh, Andrew J H Smith, Rachel L Batterham, Michael L J Ashford, Bart Vanhaesebroeck, Dominic J Withers

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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 p110alpha or p110beta PI3K catalytic subunits in these neurons and demonstrate a dominant role for the latter in energy homeostasis regulation. In POMC neurons, p110beta inactivation prevented insulin- and leptin-stimulated electrophysiological responses. POMCp110beta null mice exhibited central leptin resistance, increased adiposity, and diet-induced obesity. In contrast, the response to leptin was not blocked in p110alpha-deficient POMC neurons. Accordingly, POMCp110alpha null mice displayed minimal energy homeostasis abnormalities. Similarly, in AgRP neurons, p110beta had a more important role than p110alpha. AgRPp110alpha null mice displayed normal energy homeostasis regulation, whereas AgRPp110beta null mice were lean, with increased leptin sensitivity and resistance to diet-induced obesity. These results demonstrate distinct metabolic roles for the p110alpha and p110beta isoforms of PI3K in hypothalamic energy regulation.
Original languageEnglish
Pages (from-to)343-354
Number of pages12
JournalCell Metabolism
Volume10
Issue number5
DOIs
Publication statusPublished - 4 Nov 2009

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Keywords

  • humdisease

Cite this

Al-Qassab, H., Smith, M. A., Irvine, E. E., Guillermet-Guibert, J., Claret, M., Choudhury, A. I., ... Withers, D. J. (2009). Dominant role of the p110β isoform of PI3K over p110alpha in energy homeostasis regulation by POMC and AgRP neurons. Cell Metabolism, 10(5), 343-354. https://doi.org/10.1016/j.cmet.2009.09.008