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Role of Neuronal Glucosensing in the Regulation of Energy Homeostasis Barry E

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Role of Neuronal Glucosensing in the Regulation of Energy Homeostasis Barry E Role of Neuronal Glucosensing in the Regulation of Energy Homeostasis Barry E. Levin,1,2 Ling Kang,2 Nicole M. Sanders,3 and Ambrose A. Dunn-Meynell1,2 Glucosensing is a property of specialized neurons in the studies of damage to the hypothalamus pointed to the brain that regulate their membrane potential and firing brain as the primary regulator of energy homeostasis. rate as a function of ambient glucose levels. These neurons Lesions of the ventromedial hypothalamus (VMH) produce have several similarities to ␤- and ␣-cells in the pancreas, increased food intake (hyperphagia), obesity (1), and which are also responsive to ambient glucose levels. Many defective autonomic function in organs involved in the use glucokinase as a rate-limiting step in the production of ATP and its effects on membrane potential and ion channel regulation of energy expenditure (2,3). On the other hand, function to sense glucose. Glucosensing neurons are orga- electrical stimulation of the VMH leads to generalized nized in an interconnected distributed network throughout sympathoadrenal activation (4) with increased activity in the brain that also receives afferent neural input from thermogenic tissues (5). Lesions of the lateral hypotha- glucosensors in the liver, carotid body, and small intes- lamic area (LHA) reduce food intake and increase sympa- tines. In addition to glucose, glucosensing neurons can use thetic activity and eventually establish a new lower other metabolic substrates, hormones, and peptides to defended body weight (3,5,6). Whereas such early studies regulate their firing rate. Consequently, the output of pointed to the hypothalamus as the central controller of these “metabolic sensing” neurons represents their in- tegrated response to all of these simultaneous inputs. energy homeostasis, later studies suggested that energy The efferents of these neurons regulate feeding, neu- homeostasis is controlled by a distributed network of roendocrine and autonomic function, and thereby energy specialized neurons that use glucose, as well as a variety of expenditure and storage. Thus, glucosensing neurons play metabolic substrates and hormones, to regulate their a critical role in the regulation of energy homeostasis. membrane potential and firing rate (7–14) (Fig. 1). Defects in the ability to sense glucose and regulatory These “glucosensing” neurons are localized in a variety hormones like leptin and insulin may underlie the predis- of brain sites that are involved in the regulation of energy position of some individuals to develop diet-induced obe- sity. Diabetes 55 (Suppl. 2):S122–S130, 2006 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 he term “energy homeostasis” is a modification (17). Their vagal and sympathetic neural afferents termi- of the second law of thermodynamics whereby nate predominantly in the nucleus tractus solitarius (NTS) the amount of energy taken in as food equals the in the medulla (Fig. 1). The neurons in the NTS represent Tamount expended as heat (thermogenesis). a critical nodal point where hardwired inputs from meta- When intake exceeds expenditure, the excess is stored bolic, hormone, and peptide signals from the periphery primarily as glycogen and fat, and these stores are used to converge and are integrated. Because many NTS neurons supply fuel when food is in short supply. This process is are also glucosensing neurons, this allows them to sum- regulated over different time frames and by a variety of mate the direct effects of glucose, other metabolic sub- physiological and metabolic systems; dysregulation of strates, and hormones such as leptin and insulin at the either intake or expenditure can lead to obesity. Early level of their membrane potential with those arriving via neural afferents from peripheral glucosensors (18). NTS From the 1Neurology Service, Department of Veterans Affairs New Jersey neurons project widely to other brainstem and forebrain Health Care System, East Orange, New Jersey; the 2Department of Neurology nuclei such as the rostral and caudal ventrolateral medulla and Neurosciences, New Jersey Medical School, University of Medicine and and raphe pallidus and obscurus (RPa/Ob); the hypotha- Dentistry, Newark, New Jersey; and the 3VA Puget Sound Health Care System, Metabolism and Endocrinology Division and Department of Psychiatry and lamic paraventricular nucleus (PVN), arcuate nucleus Behavioral Sciences, University of Washington, Seattle, Washington. (ARC), ventromedial nucleus (VMN), and dorsomedial Address correspondence and reprint requests to Barry E. Levin, Neurology nucleus; and LHA, the substantia nigra, and ventral teg- Service (127C), VA Medical Center, 385 Tremont Ave., East Orange, NJ 07018. E-mail: [email protected]. mental and central nucleus of the amygdala, most of which Received for publication 22 March 2006 and accepted in revised form 15 contain glucosensing neurons and are also involved in May 2006. autonomic function and energy homeostasis (Figs. 1 and 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- 2) (19–22). tional grant from Servier. Because of historical precedents, a majority of early 5TG, 5-thioglucose; ARC, arcuate nucleus; CRR, counterregulatory re- studies focused on hypothalamic neurons as regulators of sponse; GE, glucose excited; GI, glucose inhibited; GK, glucokinase; KATP channel, ATP-sensitive Kϩ channel; LHA, lateral hypothalamic area; NPY, energy homeostasis. This has led to the realization that neuropeptide Y; NTS, nucleus tractus solitarius; POMC, proopiomelanocortin; manipulations of the VMH most often affected function in PVN, paraventricular nucleus; VMH, ventromedial hypothalamus; VMN, ven- both the VMN and ARC (Fig. 2). In fact, it is the ARC that tromedial nucleus. DOI: 10.2337/db06-S016 may be the more important of these two nuclei, since it © 2006 by the American Diabetes Association. contains two sets of neurons whose primary function 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 appears to be the regulation of energy homeostasis. Medial with 18 U.S.C. Section 1734 solely to indicate this fact. ARC neurons that express neuropeptide Y (NPY) are S122 DIABETES, VOL. 55, SUPPLEMENT 2, DECEMBER 2006 B.E. LEVIN AND ASSOCIATES FIG. 1. Location and afferent inputs to central glucosensing neurons. Vagal, glossopharyngeal, and sympathetic afferents from metabolic sensors (denoted by four-pointed stars) in the portal vein, carotid body, stomach, and small intestines converge on NTS metabolic sensing neurons (denoted by five-pointed stars) in the medulla and are integrated along with metabolic and hormonal signals from the periphery, which are transported across the blood-brain barrier or cross through the fenestrated barrier in the area postrema adjacent to the NTS. In addition to the NTS, noradrenergic, adrenergic, neuropeptide Y (NPY), glucagon-like peptide 1 (GLP-1), and ␣-melanocyte–stimulating hormone (␣-MSH) metabolic sensing neurons in the caudal ventrolateral medulla (CVLM) and rostral ventrolateral medulla (RVLM) also integrate these incoming signals and project to various hypothalamic nuclei (arcuate [ARC], ventromedial [VMN], dorsomedial [DMN], paraventricular [PVN]) and the LHA. Metabolic sensing serotonin neurons in the raphe pallidus and obscurus (RPa/Ob) project to sympathetic preganglionic neurons in the intermediolateral cell column of the spinal cord. Metabolites and hormones also interact with metabolic sensing neurons in the hypothalamus. Neurons in the ARC project to additional metabolic sensing neurons in the PVN and LHA, and the LHA also projects to the PVN, which, along with the LHA, gives rise to descending outputs to autonomic outs in the medulla and spinal cord. Adrenal medullary cells also are responsive to low glucose levels as one possible mechanism for their release of epinephrine to mobilize hepatic glucose stores during hypoglycemia (L.K., B.E.L., unpublished data). Dotted lines denote polysynaptic pathways. classified as anabolic because release of this peptide onto both leptin and insulin inhibit NPY and stimulate POMC target neurons in the PVN and LHA potently stimulates gene transcription. Insulin and leptin also have acute food intake and inhibits energy expenditure by decreasing effects on NPY and POMC neuronal activity (19). sympathetic activity in thermogenic organs. Laterally Two other groups of metabolic sensing neurons in the placed ARC neurons produce proopiomelanocortin LHA produce the anabolic peptides orexin (hypocretin) (POMC), which is a pro-hormone for ␣-melanocyte–stim- and melanocyte concentrating hormones. As opposed to ulating hormone. This catabolic peptide interacts with ARC NPY and POMC neurons, these LHA neurons are melanocortin 3 and 4 receptors (MC3/4-R) to inhibit intake involved in a much wider spectrum of metabolic, physio- and stimulate sympathetic activity and thermogenesis by logical, and behavioral processes (24,25) (Fig. 2). Orexin acting on some of the same PVN and LHA neurons that are neurons are inhibited (glucose-inhibited [GI] neurons) and NPY targets. Some ARC POMC neurons also project to the melanocyte concentrating hormone neurons are excited intermedio-lateral cell column
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