Dominant role of the p110beta isoform of PI3K over p110alpha 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 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.
Al-Qassab
Hind
H
Centre for Diabetes and Endocrinology, Rayne Institute, University College London, London WC1E 6JJ, UK.
Smith
Mark A
MA
Irvine
Elaine E
EE
Guillermet-Guibert
Julie
J
Claret
Marc
M
Choudhury
Agharul I
AI
Selman
Colin
C
Piipari
Kaisa
K
Clements
Melanie
M
Lingard
Steven
S
Chandarana
Keval
K
Bell
Jimmy D
JD
Barsh
Gregory S
GS
Smith
Andrew J H
AJ
Batterham
Rachel L
RL
Ashford
Michael L J
ML
Vanhaesebroeck
Bart
B
Withers
Dominic J
DJ
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
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