title: DRP1 Suppresses Leptin and Glucose Sensing of POMC Neurons.
abstract: Hypothalamic pro-opiomelanocortin (POMC) neurons regulate energy and glucose metabolism. Intracellular mechanisms that enable these neurons to respond to changes in metabolic environment are ill defined. Here we show reduced expression of activated dynamin-related protein (pDRP1), a mitochondrial fission regulator, in POMC neurons of fed mice. These POMC neurons displayed increased mitochondrial size and aspect ratio compared to POMC neurons of fasted animals. Inducible deletion of DRP1 of mature POMC neurons (Drp1fl/fl-POMC-cre:ERT2) resulted in improved leptin sensitivity and glucose responsiveness. In Drp1fl/fl-POMC-cre:ERT2mice, POMC neurons showed increased mitochondrial size, ROS production, and neuronal activation with increased expression of Kcnj11 mRNA regulated by peroxisome proliferator-activated receptor (PPAR). Furthermore, deletion of DRP1 enhanced the glucoprivic stimulus in these neurons, causing their stronger inhibition and a greater activation of counter-regulatory responses to hypoglycemia that were PPAR dependent. Together, these data unmasked a role for mitochondrial fission in leptin sensitivity and glucose sensing of POMC neurons.
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Anna
authors.initials: A
authors.lastname: Santoro
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Michela
authors.initials: M
authors.lastname: Campolo
authors.affiliation: Department of Internal Medicine, Division of Hypothalamic Research, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Cell Biology, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Sesaki
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Pharmacy, University of Naples "Federico II," 80131 Napoli, Italy.
authors.forename: Rosaria
authors.initials: R
authors.lastname: Meli
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Zhong-Wu
authors.initials: ZW
authors.lastname: Liu
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA.
authors.forename: Jung Dae
authors.initials: JD
authors.lastname: Kim
authors.affiliation: Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of Medicine, New Haven, CT 06520, USA; Department of Neuroscience, Yale University School of Medicine, New Haven, CT 06520, USA; Section of Comparative Medicine, Yale University School of Medicine, New Haven, CT 06520, USA. Electronic address: sabrina.diano@yale.edu.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Diano
mesh_terms: D000818:Animals; D034281:Dynamins / Q000378:metabolism*; D004734:Energy Metabolism; D005247:Feeding Behavior; D017353:Gene Deletion; D005947:Glucose / Q000378:metabolism*; D007003:Hypoglycemia / Q000378:metabolism / Q000473:pathology; D020738:Leptin / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism / Q000648:ultrastructure; D009474:Neurons / Q000378:metabolism*; D047495:PPAR gamma / Q000378:metabolism; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D000099161:Kcnj11 Channel
chemical_list: D034281:Dynamins; D005947:Glucose; D020738:Leptin; D047495:PPAR gamma; D024661:Potassium Channels, Inwardly Rectifying; D011333:Pro-Opiomelanocortin; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D000099161:Kcnj11 Channel; C486391:Dnm1l protein, mouse
keywords: Drp1; POMC neurons; counter-regulatory responses to hypoglycemia; glucose sensing; leptin; mitochondrial fission