Dominant role of the p110β isoform of PI3K over p110α in energy homeostasis regulation by POMC and AgRP neurons

Al-Qassab, H. et al. (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. (doi: 10.1016/j.cmet.2009.09.008)

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.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Selman, Professor Colin
• Authors: Al-Qassab, H., Smith, M.A., Irvine, E.E., Guillermet-Guibert, J., Claret, M., Choudhury, A.I., Selman, C., Piipari, K., Clements, M., Lingard, S., Chandarana, K., Bell, J.D., Barsh, G.S., Smith, A.J.H., Batterham, R.L., Ashford, M.L.J., Vanhaesebroeck, B., and Withers, D.J.
• College/School: College of Medical Veterinary and Life Sciences > School of Biodiversity, One Health & Veterinary Medicine
• Journal Name: Cell Metabolism
• ISSN: 1550-4131
• ISSN (Online): 1932-7420