Neuronal Rap1 Regulates Energy Balance, Glucose Homeostasis, and Leptin Actions

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dc.contributor.authorKaneko, Kentaroen
dc.contributor.authorXu, Pingwenen
dc.contributor.authorCordonier, Elizabeth L.en
dc.contributor.authorChen, Siyu S.en
dc.contributor.authorNg, Amyen
dc.contributor.authorXu, Yongen
dc.contributor.authorMorozov, Alexeien
dc.contributor.authorFukuda, Makotoen
dc.date.accessioned2019-05-29T16:26:02Zen
dc.date.available2019-05-29T16:26:02Zen
dc.date.issued2016-09-13en
dc.description.abstractThe CNS contributes to obesity and metabolic disease; however, the underlying neurobiological pathways remain to be fully established. Here, we show that the small GTPase Rap1 is expressed in multiple hypothalamic nuclei that control whole-body metabolism and is activated in high-fat diet (HFD)-induced obesity. Genetic ablation of CNS Rap1 protects mice from dietary obesity, glucose imbalance, and insulin resistance in the periphery and from HFD-induced neuropathological changes in the hypothalamus, including diminished cellular leptin sensitivity and increased endoplasmic reticulum (ER) stress and inflammation. Furthermore, pharmacological inhibition of CNS Rap1 signaling normalizes hypothalamic ER stress and inflammation, improves cellular leptin sensitivity, and reduces body weight in mice with dietary obesity. We also demonstrate that Rap1 mediates leptin resistance via interplay with ER stress. Thus, neuronal Rap1 critically regulates leptin sensitivity and mediates HFD-induced obesity and hypothalamic pathology and may represent a potential therapeutic target for obesity treatment.en
dc.description.notesThe authors gratefully acknowledge Zainab Mabizari for technical assistance; Drs. Joel K. Elmquist and Takashi Kadowaki for helpful discussion during the course of this study; Qingchun Tong, Miao-Hsueh Chen, and Tuo Deng for comments on the manuscript; Mr. Mark Meyer for editing the manuscript; and Dr. Marta L. Fiorotto for interpretive assistance. This work was supported by USDA CRIS 6250-51000-055, AHA-14BGIA20460080, NIH-P30-DK079638, and NIH R01DK104901 (to M.F.); NIH Awards R01DK093587 and R01DK101379 (to Y.X.); AHA-15POST22500012 and Uehara Memorial Foundation 201340214 (to K.K.); and NIH T32HD071839 (to E.L.C.).en
dc.description.sponsorshipUSDA [CRIS 6250-51000-055, AHA-14BGIA20460080, NIH-P30-DK079638, NIH R01DK104901]; NIH [R01DK093587, R01DK101379, AHA-15POST22500012, T32HD071839]; Uehara Memorial Foundation [201340214]en
dc.format.mimetypeapplication/pdfen
dc.identifier.doihttps://doi.org/10.1016/j.celrep.2016.08.039en
dc.identifier.issn2211-1247en
dc.identifier.issue11en
dc.identifier.pmid27626668en
dc.identifier.urihttp://hdl.handle.net/10919/89633en
dc.identifier.volume16en
dc.publisherElsevieren
dc.rightsCreative Commons Attribution-NonCommercial-NoDerivatives 4.0 Internationalen
dc.rights.urihttp://creativecommons.org/licenses/by-nc-nd/4.0/en
dc.subjectEndoplasmic-Reticulum Stressen
dc.subjectDiet-Induced Obesityen
dc.subjectNervous-System Controlen
dc.subjectConnects Er Stressen
dc.subjectBody-Weighten
dc.subjectCyclic-Ampen
dc.subjectInsulin-Resistanceen
dc.subjectFood-Intakeen
dc.subjectMiceen
dc.subjectCampen
dc.titleNeuronal Rap1 Regulates Energy Balance, Glucose Homeostasis, and Leptin Actionsen
dc.title.serialCell Reportsen
dc.typeArticle - Refereeden
dc.type.dcmitypeTexten

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Destination Area: Adaptive Brain and Behavior (ABB)