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Role of Neuronal Glucosensing in the Regulation of Energy Homeostasis

¹ Neurology Service, Department of Veterans Affairs New Jersey Health Care System, East Orange, New Jersey
² Department of Neurology and Neurosciences, New Jersey Medical School, University of Medicine and Dentistry, Newark, New Jersey
³ VA Puget Sound Health Care System, Metabolism and Endocrinology Division and Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington

Address correspondence and reprint requests to Barry E. Levin, Neurology Service (127C), VA Medical Center, 385 Tremont Ave., East Orange, NJ 07018. E-mail: levin{at}umdnj.edu

Abbreviations: 5TG, 5-thioglucose; ARC, arcuate nucleus; CRR, counterregulatory response; GE, glucose excited; GI, glucose inhibited; GK, glucokinase; K_ATP channel, ATP-sensitive K⁺ channel; LHA, lateral hypothalamic area; NPY, neuropeptide Y; NTS, nucleus tractus solitarius; POMC, proopiomelanocortin; PVN, paraventricular nucleus; VMH, ventromedial hypothalamus; VMN, ventromedial nucleus

Glucosensing is a property of specialized neurons in the brain that regulate their membrane potential and firing rate as a function of ambient glucose levels. These neurons have several similarities to ß- and -cells in the pancreas, which are also responsive to ambient glucose levels. Many use glucokinase as a rate-limiting step in the production of ATP and its effects on membrane potential and ion channel function to sense glucose. Glucosensing neurons are organized in an interconnected distributed network throughout the brain that also receives afferent neural input from glucosensors in the liver, carotid body, and small intestines. In addition to glucose, glucosensing neurons can use other metabolic substrates, hormones, and peptides to regulate their firing rate. Consequently, the output of these "metabolic sensing" neurons represents their integrated response to all of these simultaneous inputs. The efferents of these neurons regulate feeding, neuroendocrine and autonomic function, and thereby energy expenditure and storage. Thus, glucosensing neurons play a critical role in the regulation of energy homeostasis. Defects in the ability to sense glucose and regulatory hormones like leptin and insulin may underlie the predisposition of some individuals to develop diet-induced obesity.

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