title: Dominant role of the p110beta isoform of PI3K over p110alpha in energy homeostasis regulation by POMC and AgRP neurons.
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.
authors.affiliation: Centre for Diabetes and Endocrinology, Rayne Institute, University College London, London WC1E 6JJ, UK.
authors.forename: Hind
authors.initials: H
authors.lastname: Al-Qassab
authors.forename: Mark A
authors.initials: MA
authors.lastname: Smith
authors.forename: Elaine E
authors.initials: EE
authors.lastname: Irvine
authors.forename: Julie
authors.initials: J
authors.lastname: Guillermet-Guibert
authors.forename: Marc
authors.initials: M
authors.lastname: Claret
authors.forename: Agharul I
authors.initials: AI
authors.lastname: Choudhury
authors.forename: Colin
authors.initials: C
authors.lastname: Selman
authors.forename: Kaisa
authors.initials: K
authors.lastname: Piipari
authors.forename: Melanie
authors.initials: M
authors.lastname: Clements
authors.forename: Steven
authors.initials: S
authors.lastname: Lingard
authors.forename: Keval
authors.initials: K
authors.lastname: Chandarana
authors.forename: Jimmy D
authors.initials: JD
authors.lastname: Bell
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Barsh
authors.forename: Andrew J H
authors.initials: AJ
authors.lastname: Smith
authors.forename: Rachel L
authors.initials: RL
authors.lastname: Batterham
authors.forename: Michael L J
authors.initials: ML
authors.lastname: Ashford
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
authors.forename: Dominic J
authors.initials: DJ
authors.lastname: Withers
mesh_terms: D050154:Adiposity / Q000235:genetics; D054369:Agouti-Related Protein / Q000378:metabolism*; D000818:Animals; D058534:Class I Phosphatidylinositol 3-Kinases; D004032:Diet; D055724:Electrophysiological Phenomena; D004734:Energy Metabolism / Q000502:physiology*; D007031:Hypothalamus / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020738:Leptin / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D055099:Neuroendocrine Cells / Q000201:enzymology; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D015398:Signal Transduction
chemical_list: D054369:Agouti-Related Protein; D058534:Class I Phosphatidylinositol 3-Kinases; D007328:Insulin; D007527:Isoenzymes; D020738:Leptin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011333:Pro-Opiomelanocortin; C509622:1-phosphatidylinositol 3-kinase p110 subunit, mouse