title: Deletion of Protein Kinase C λ in POMC Neurons Predisposes to Diet-Induced Obesity.
abstract: Effectors of the phosphoinositide 3-kinase (PI3K) signal transduction pathway contribute to the hypothalamic regulation of energy and glucose homeostasis in divergent ways. Here we show that central nervous system (CNS) action of the PI3K signaling intermediate atypical protein kinase C (aPKC) constrains food intake, weight gain, and glucose intolerance in both rats and mice. Pharmacological inhibition of CNS aPKC activity acutely increases food intake and worsens glucose tolerance in chow-fed rodents and causes excess weight gain during high-fat diet (HFD) feeding. Similarly, selective deletion of the aPKC isoformPkc-λin proopiomelanocortin (POMC) neurons disrupts leptin action, reduces melanocortin content in the paraventricular nucleus, and markedly increases susceptibility to obesity, glucose intolerance, and insulin resistance specifically in HFD-fed male mice. These data implicate aPKC as a novel regulator of energy and glucose homeostasis downstream of the leptin-PI3K pathway in POMC neurons.
authors.affiliation: UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, WA.
authors.forename: Mauricio D
authors.initials: MD
authors.lastname: Dorfman
authors.affiliation: UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, WA.
authors.forename: Jordan E
authors.initials: JE
authors.lastname: Krull
authors.affiliation: UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, WA.
authors.forename: Jarrad M
authors.initials: JM
authors.lastname: Scarlett
authors.affiliation: UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, WA.
authors.forename: Stephan J
authors.initials: SJ
authors.lastname: Guyenet
authors.affiliation: Department of Internal Medicine, University of South Florida College of Medicine, Tampa, FL.|Research & Internal Medicine Services, James A. Haley VA Medical Center, Tampa, FL.
authors.forename: Mini P
authors.initials: MP
authors.lastname: Sajan
authors.affiliation: UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, WA.
authors.forename: Vincent
authors.initials: V
authors.lastname: Damian
authors.affiliation: UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, WA.
authors.forename: Hong T
authors.initials: HT
authors.lastname: Nguyen
authors.affiliation: The Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway.
authors.forename: Michael
authors.initials: M
authors.lastname: Leitges
authors.affiliation: UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, WA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Morton
authors.affiliation: Department of Internal Medicine, University of South Florida College of Medicine, Tampa, FL.|Research & Internal Medicine Services, James A. Haley VA Medical Center, Tampa, FL.
authors.forename: Robert V
authors.initials: RV
authors.lastname: Farese
authors.affiliation: UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, WA.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Schwartz
authors.affiliation: UW Diabetes Institute and Department of Medicine, University of Washington, Seattle, WA jpthaler@uw.edu.
authors.forename: Joshua P
authors.initials: JP
authors.lastname: Thaler
mesh_terms: D000818:Animals; D059305:Diet, High-Fat; D004435:Eating / Q000187:drug effects / Q000235:genetics*; D004734:Energy Metabolism / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000378:metabolism*; D018149:Glucose Intolerance / Q000235:genetics* / Q000378:metabolism; D007031:Hypothalamus / Q000378:metabolism; D007333:Insulin Resistance; D007527:Isoenzymes / Q000235:genetics*; D020738:Leptin / Q000378:metabolism; D008297:Male; D053486:Melanocortins / Q000378:metabolism; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D009765:Obesity / Q000235:genetics* / Q000378:metabolism; D010286:Paraventricular Hypothalamic Nucleus / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000187:drug effects / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D015430:Weight Gain / Q000187:drug effects / Q000235:genetics*; D000099293:Protein Kinase C-lambda
chemical_list: D005947:Glucose; D007527:Isoenzymes; D020738:Leptin; D053486:Melanocortins; D019869:Phosphatidylinositol 3-Kinases; D011333:Pro-Opiomelanocortin; D011493:Protein Kinase C; D000099293:Protein Kinase C-lambda; C115015:PKC-3 protein