Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity.
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.
Parton
Laura E
LE
Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center and Harvard Medical School, 99 Brookline Avenue, Boston, Massachusetts 02215, USA.
Ye
Chian Ping
CP
Coppari
Roberto
R
Enriori
Pablo J
PJ
Choi
Brian
B
Zhang
Chen-Yu
CY
Xu
Chun
C
Vianna
Claudia R
CR
Balthasar
Nina
N
Lee
Charlotte E
CE
Elmquist
Joel K
JK
Cowley
Michael A
MA
Lowell
Bradford B
BB
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
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