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Role of Neuronal Glucosensing in the Regulation of Energy Homeostasis 1,2 2 3 1,2 Barry E. Levin, Ling Kang, Nicole M. Sanders, and Ambrose A. Dunn-Meynell
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- 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 orga-nized in an interconnected distributed network throughout the brain that also receives afferent neural input from glucosensors in the liver, carotid body, and small intes-tines. 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 in-tegrated response to all of these simultaneous inputs. The efferents of these neurons regulate feeding, neu-roendocrine 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 predis-position of some individuals to develop diet-induced obe-sity.Diabetes55 (Suppl. 2):S122–S130, 2006
he term “energy homeostasis” is a modification of the second law of thermodynamics whereby primTarily as glycogen and fat, and these stores are used to the amount of energy taken in as food equals the amount expended as heat (thermogenesis). When intake exceeds expenditure, the excess is stored supply fuel when food is in short supply. This process is regulated over different time frames and by a variety of physiological and metabolic systems; dysregulation of either intake or expenditure can lead to obesity. Early
1 From the Neurology Service, Department of Veterans Affairs New Jersey 2 Health Care System, East Orange, New Jersey; the Department of Neurology and Neurosciences, New Jersey Medical School, University of Medicine and 3 Dentistry, Newark, New Jersey; and the 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@umdnj.edu. Received for publication 22 March 2006 and accepted in revised form 15 May 2006. This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educa tional grant from Servier. 5TG, 5thioglucose; ARC, arcuate nucleus; CRR, counterregulatory re sponse; 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, ven tromedial nucleus. DOI: 10.2337/db06S016 © 2006 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
studies of damage to the hypothalamus pointed to the brain as the primary regulator of energy homeostasis. Lesions of the ventromedial hypothalamus (VMH) produce increased food intake (hyperphagia), obesity (1), and defective autonomic function in organs involved in the regulation of energy expenditure (2,3). On the other hand, electrical stimulation of the VMH leads to generalized sympathoadrenal activation (4) with increased activity in thermogenic tissues (5). Lesions of the lateral hypotha lamic area (LHA) reduce food intake and increase sympa thetic activity and eventually establish a new lower defended body weight (3,5,6). Whereas such early studies pointed to the hypothalamus as the central controller of energy homeostasis, later studies suggested that energy homeostasis is controlled by a distributed network of specialized neurons that use glucose, as well as a variety of metabolic substrates and hormones, to regulate their membrane potential and firing rate (7–14) (Fig. 1). These “glucosensing” neurons are localized in a variety of brain sites that are involved in the regulation of energy homeostasis. These central neurons are part of a larger network of glucosensors that are located in peripheral organs. Such peripheral glucosensors are located in the hepatic portal vein (15), carotid body (16), and the gut (17). Their vagal and sympathetic neural afferents termi nate predominantly in the nucleus tractus solitarius (NTS) in the medulla (Fig. 1). The neurons in the NTS represent a critical nodal point where hardwired inputs from meta bolic, hormone, and peptide signals from the periphery converge and are integrated. Because many NTS neurons are also glucosensing neurons, this allows them to sum mate the direct effects of glucose, other metabolic sub strates, and hormones such as leptin and insulin at the level of their membrane potential with those arriving via neural afferents from peripheral glucosensors (18). NTS neurons project widely to other brainstem and forebrain nuclei such as the rostral and caudal ventrolateral medulla and raphe pallidus and obscurus (RPa/Ob); the hypotha lamic paraventricular nucleus (PVN), arcuate nucleus (ARC), ventromedial nucleus (VMN), and dorsomedial nucleus; and LHA, the substantia nigra, and ventral teg mental and central nucleus of the amygdala, most of which contain glucosensing neurons and are also involved in autonomic function and energy homeostasis (Figs. 1 and 2) (19 –22). Because of historical precedents, a majority of early studies focused on hypothalamic neurons as regulators of energy homeostasis. This has led to the realization that manipulations of the VMH most often affected function in both the VMN and ARC (Fig. 2). In fact, it is the ARC that may be the more important of these two nuclei, since it contains two sets of neurons whose primary function appears to be the regulation of energy homeostasis. Medial ARC neurons that express neuropeptide Y (NPY) are