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Phosphatidyl Inositol 3-Kinase Signaling in Hypothalamic Proopiomelanocortin Neurons Contributes to the Regulation of Glucose Homeostasis

Division of Hypothalamic Research (J.W.H., Y.X., R.C., J.K.E.), Department of Internal Medicine and Pharmacology, Department of Internal Medicine and Cell Biology (Y.-R.C.), Touchstone Center for Diabetes Research, The University of Texas Southwestern Medical Center, Dallas, Texas 75390; Cardiomet Mouse Metabolic Facility (F.P.), Center for Integrative Genomics, University of Lausanne, CH-1015 Lausanne, Switzerland; Departments of Genetics (J.L.), Systems Biology (L.C.C.), and Pathology (J.J.Z.), Harvard Medical School, Department of Medicine (J.L.), Brigham and Women’s Hospital, and Divisions of Signal Transduction (L.C.C.) and Endocrinology (B.B.K.), Beth Israel Deaconess Medical Center, and Department of Cancer Biology (J.J.Z.), Dana-Farber Cancer Institute, Boston, Massachusetts 02215; and Division of Physiology (N.B.), University of Bristol, Bristol BS8 1TD, United Kingdom

Address all correspondence and requests for reprints to: Joel Elmquist, Division of Hypothalamic Research, Department of Internal Medicine, The University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9077. E-mail: joel.elmquist{at}utsouthwestern.edu; or Jean Zhao, Dana-Farber Cancer Institute, 44 Binney Street, Smith 936B, Boston, Massachusetts 02115. E-mail: jean_zhao{at}dfci.harvard.edu.

Recent studies demonstrated a role for hypothalamic insulin and leptin action in the regulation of glucose homeostasis. This regulation involves proopiomelanocortin (POMC) neurons because suppression of phosphatidyl inositol 3-kinase (PI3K) signaling in these neurons blunts the acute effects of insulin and leptin on POMC neuronal activity. In the current study, we investigated whether disruption of PI3K signaling in POMC neurons alters normal glucose homeostasis using mouse models designed to both increase and decrease PI3K-mediated signaling in these neurons. We found that deleting p85 alone induced resistance to diet-induced obesity. In contrast, deletion of the p110 catalytic subunit of PI3K led to increased weight gain and adipose tissue along with reduced energy expenditure. Independent of these effects, increased PI3K activity in POMC neurons improved insulin sensitivity, whereas decreased PI3K signaling resulted in impaired glucose regulation. These studies show that activity of the PI3K pathway in POMC neurons is involved in not only normal energy regulation but also glucose homeostasis.