Glucose sensing by POMC neurons regulates glucose homeostasis and is impaired in obesity

• DOI: 10.1038/nature06098
• Publication Date: 2007-08-29T18:53:34Z
• Authors: Laura E. Parton; Chian Ping Ye; Roberto Coppari; Pablo J. Enriori; Brian Choi; Chen-Yu Zhang; Chun Xu; Claudia R. Vianna; Nina Balthasar; Charlotte E. Lee; Joel K. Elmquist; Michael A. Cowley; Bradford B. Lowell
• Keywords: Mitochondrial Proteins / antagonists & inhibitors; 0301 basic medicine; 570; Pro-Opiomelanocortin; Adenosine Triphosphate / metabolism; Neurons / drug effects; Mice, Obese; Potassium Channels, Inwardly Rectifying / genetics; Mice, Transgenic; Iridoids / pharmacology; Ion Channels; Ion Channels / antagonists & inhibitors; Mitochondrial Proteins; Mice; 03 medical and health sciences; Adenosine Triphosphate; Neurons / pathology; Diabetes Mellitus, Type 2 / metabolism; Animals; Homeostasis; Humans; Iridoids; Uncoupling Protein 2; Dietary Fats / pharmacology; Pro-Opiomelanocortin / metabolism; Obesity; Potassium Channels, Inwardly Rectifying; Mitochondrial Proteins / genetics; Ion Channels / genetics; Glucose / metabolism; Neurons; 2. Zero hunger; Obesity / physiopathology; Neurons / metabolism; Potassium Channels, Inwardly Rectifying / metabolism; Dietary Fats; Ion Channels / metabolism; Diabetes Mellitus, Type 2 / physiopathology; Mitochondrial Proteins / metabolism; Glucose; Diabetes Mellitus, Type 2; Adenosine Triphosphate / biosynthesis; Obesity / metabolism; Iridoid Glycosides; Dietary Fats / administration & dosage; Obesity / chemically induced

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.