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Publication Detail
Dominant role of the p110beta isoform of PI3K over p110alpha in energy homeostasis regulation by POMC and AgRP neurons.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Journal Article
  • Authors:
    Al-Qassab H, Smith MA, Irvine EE, Guillermet-Guibert J, Claret M, Choudhury AI, Selman C, Piipari K, Clements M, Lingard S, Chandarana K, Bell JD, Barsh GS, Smith AJH, Batterham RL, Ashford MLJ, Vanhaesebroeck B, Withers DJ
  • Publication date:
    11/2009
  • Pagination:
    343, 354
  • Journal:
    Cell Metab
  • Volume:
    10
  • Issue:
    5
  • Status:
    Published
  • Country:
    United States
  • PII:
    S1550-4131(09)00296-4
  • Language:
    eng
  • Keywords:
    Adiposity, Agouti-Related Protein, Animals, Class I Phosphatidylinositol 3-Kinases, Diet, Electrophysiological Phenomena, Energy Metabolism, Hypothalamus, Insulin, Isoenzymes, Leptin, Mice, Mice, Knockout, Neuroendocrine Cells, Obesity, Phosphatidylinositol 3-Kinases, Phosphoinositide-3 Kinase Inhibitors, Pro-Opiomelanocortin, Signal Transduction
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.
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