title: Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity.
abstract: A subset of neurons in the brain, known as 'glucose-excited' neurons, depolarize and increase their firing rate in response to increases in extracellular glucose. Similar to insulin secretion by pancreatic beta-cells, glucose excitation of neurons is driven by ATP-mediated closure of ATP-sensitive potassium (K(ATP)) channels. Although beta-cell-like glucose sensing in neurons is well established, its physiological relevance and contribution to disease states such as type 2 diabetes remain unknown. To address these issues, we disrupted glucose sensing in glucose-excited pro-opiomelanocortin (POMC) neurons via transgenic expression of a mutant Kir6.2 subunit (encoded by the Kcnj11 gene) that prevents ATP-mediated closure of K(ATP) channels. Here we show that this genetic manipulation impaired the whole-body response to a systemic glucose load, demonstrating a role for glucose sensing by POMC neurons in the overall physiological control of blood glucose. We also found that glucose sensing by POMC neurons became defective in obese mice on a high-fat diet, suggesting that loss of glucose sensing by neurons has a role in the development of type 2 diabetes. The mechanism for obesity-induced loss of glucose sensing in POMC neurons involves uncoupling protein 2 (UCP2), a mitochondrial protein that impairs glucose-stimulated ATP production. UCP2 negatively regulates glucose sensing in POMC neurons. We found that genetic deletion of Ucp2 prevents obesity-induced loss of glucose sensing, and that acute pharmacological inhibition of UCP2 reverses loss of glucose sensing. We conclude that obesity-induced, UCP2-mediated loss of glucose sensing in glucose-excited neurons might have a pathogenic role in the development of type 2 diabetes.
authors.affiliation: Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, 99 Brookline Avenue, Boston, Massachusetts 02215, USA.
authors.forename: Laura E
authors.initials: LE
authors.lastname: Parton
authors.forename: Chian Ping
authors.initials: CP
authors.lastname: Ye
authors.forename: Roberto
authors.initials: R
authors.lastname: Coppari
authors.forename: Pablo J
authors.initials: PJ
authors.lastname: Enriori
authors.forename: Brian
authors.initials: B
authors.lastname: Choi
authors.forename: Chen-Yu
authors.initials: CY
authors.lastname: Zhang
authors.forename: Chun
authors.initials: C
authors.lastname: Xu
authors.forename: Claudia R
authors.initials: CR
authors.lastname: Vianna
authors.forename: Nina
authors.initials: N
authors.lastname: Balthasar
authors.forename: Charlotte E
authors.initials: CE
authors.lastname: Lee
authors.forename: Joel K
authors.initials: JK
authors.lastname: Elmquist
authors.forename: Michael A
authors.initials: MA
authors.lastname: Cowley
authors.forename: Bradford B
authors.initials: BB
authors.lastname: Lowell
mesh_terms: D000255:Adenosine Triphosphate / Q000096:biosynthesis / Q000378:metabolism; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism*; D006706:Homeostasis; D006801:Humans; D007473:Ion Channels / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D057889:Iridoid Glycosides; D039823:Iridoids / Q000494:pharmacology; D051379:Mice; D008820:Mice, Obese; D008822:Mice, Transgenic; D024101:Mitochondrial Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009765:Obesity / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology*; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000378:metabolism*; D000071246:Uncoupling Protein 2; D000099161:Kcnj11 Channel
chemical_list: D000255:Adenosine Triphosphate; D004041:Dietary Fats; D005947:Glucose; D007473:Ion Channels; D057889:Iridoid Glycosides; D039823:Iridoids; D024101:Mitochondrial Proteins; D024661:Potassium Channels, Inwardly Rectifying; D011333:Pro-Opiomelanocortin; D000071246:Uncoupling Protein 2; D000099161:Kcnj11 Channel; C000604389:UCP2 protein, human; C000604390:Ucp2 protein, mouse; C007834:genipin