Hunger and Satiety: A View From the Brain

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The Control of Food and Fluid Intake in Health and Disease, edited by Michael J. G. Farthing and Dilip Mahalanabis. Nestle Nutrition Workshop Series, Pediatric Program, Vol. 51, Nestec Ltd., Vevey/Lippincott
The Control of Food and Fluid Intake in Health and Disease, edited by Michael J. G. Farthing and Dilip Mahalanabis. Nestle Nutrition Workshop Series, Pediatric Program, Vol. 51, Nestec Ltd., Vevey/Lippincott Williams & Wilkins, Philadelphia Hunger and Satiety: A View From the Brain Gareth Williams, Joanne Harrold, and Chen Bing Department of Medicine, Diabetes and Endocrinology Research Group, University Hospital Aintree, Liverpool, England, UK The regulation of energy homeostasis is an area that straddles neurobiology, classical endocrinology, and metabolism. It is currently one of the most exciting and rapidly advancing topics in biomedical research; it is also one of the most frustrating, because the numerous leaps in scientific understanding have not yet been rewarded by any major breakthrough in the practical treatment of human nutritional disorders. Foremost among these is obesity, which is fast tightening its grip on mankind and is threatening to become one of the greatest threats to global health of the new millennium. Here, we shall review some recent progress in understanding how the body's energy stores and nutritional status are able to signal their presence to the brain, and the mechanisms through which the brain senses and responds to these signals. Much of this work has, necessarily, been performed in rodents, but some of the lessons learned in lower mammals may also apply to man although the strength and emphasis of the message may differ between the species. We shall begin by describing the basic structure of the hypothalamus, the main area involved in energy homeostasis in both rodents and man. This provides an anatomic framework for the neuronal populations, identified by the specific neurotransmitters which they express, which are important in sensing and integrating nutritional signals and in translating these inputs into appropriate changes in feeding behavior and energy expenditure. At the end of the review, we shall discuss some possible therapeutic avenues that may be opened up by this research. NEUROANATOMY OF ENERGY HOMEOSTASIS The basic organization of the rat hypothalamus is illustrated in Fig. 1. The arcuate nucleus (ARC) lies in the floor of the third ventricle immediately above the median eminence (ME), and occupies almost half the length of the hypothalamus. The ARC contains several functionally discrete populations of neurons, including one that expresses the orexigenic (appetite-stimulating) neuropeptides, neuropeptide Y (NPY) and agouti-related peptide (AGRP), and another that contains pro-opiomelanocortin (POMC) and cocaine- and amphetamine-related transcript (CART), which 45 46 HUNGER AND SATIETY: A VIEW FROM THE BRAIN PVX LHA DMH VMH ME ARC B anterior commissure 3 rd ventricle PVX SON optic chiasm ARC ME FIG. 1. Anatomy of the rat hypothalamus. (A) Coronal section of the hypothalamus showing the relative positions of the arcuate nucleus (ARC), ventromedial hypothalamic nucleus (VMH), dorsomedial hypothalamic nucleus (DMH), paraventricular nucleus (PVN), and lateral hypothalamic area (LHA) with respect to each other through the brain. (B) Sagittal section showing the main neuropeptide Y (NPY)-containing pathways in the hypothalamus, with NPYergic inputs ascending from the medulla. Potential inhibitors (-) and stimulators (+) of the ARC-NPY neurons are shown. Adapted from Williams G, Wilding J. The central nervous system and diabetes mellitus. In: Pickup JC, Williams G, eds. Textbook of diabetes. 2nd ed., vol. 2. London: Blackwell, 1997: , with permission. both act to inhibit food intake (1). The ARC and ME he within the mediobasal hypothalamus, where the blood-brain barrier (BBB) is specially modified to render this region readily accessible to circulating hormones such as leptin, insulin, ghrelin, and the glucocorticoids. As will be discussed, these are all involved in signaling nutritional state and in regulating appetite. The ARC has extensive reciprocal connections with other hypothalamic regions that control energy balance, including the paraventricular nuclei (PVN), ventromedial hypothalamic (VMH) and dorsomedial hypothalamic (DMH) nuclei; and the lateral hypothalamic area (LHA). HUNGER AND SATIETY: A VIEW FROM THE BRAIN 47 The PVN, located beside the top of the third ventricle in the anterior hypothalamus, is the site of convergence for many neuronal pathways that regulate energy homeostasis; these include projections from the NPY/AGRP and POMC/CART neurons in the ARC, and from the orexin neurons of the LHA. The PVN also contains neurons that express corticotropin-releasing factor, an appetite-inhibiting peptide that is released in the ARC and apparently acts to inhibit the NPY neurons. Neuronal pathways project from the PVN to the vagal nuclei of the medulla, which in turn innervate the islets of Langerhans; injection of various neurotransmitters into the PVN can modulate insulin and glucagon secretion (2). Lesions of the PVN result in hyperphagia, reduced energy expenditure, and obesity (3). The large VMH was long considered to be a satiety center , because stimulation of the nucleus inhibits feeding, while lesions in the region result in hyperphagia and weight gain (4). Although this hypothesis now appears to be over-simplistic, recent studies have shown that the long isoform of the leptin receptor (Ob-Rb) is highly abundant in VMH neurons (5), suggesting that this region is an important target for circulating leptin, the adipocyte-derived hormone, which acts on the brain to inhibit feeding. The VMH has direct connections with the PVN and DMH and through them, may connect indirectly with the LHA. The diffuse LHA contains separate populations of neurons that express the orexigenic peptides, Orexin A and melanin-concentrating hormone (MCH). NPY terminals are abundant in the LHA where they form synaptic connections with the Orexin and MCH cell bodies, and this region is rich in the NPY Y5 receptors that are proposed to mediate the appetite-stimulating effects of NPY (6). The LHA was viewed classically as a 'feeding center', whose actions oppose those of the VMH: electrical stimulation of this region increases food intake, while damage here can lead to fatal anorexia and wasting. This area is also rich in glucose-sensitive neurons (GSN) that are excited by a decrease in blood glucose concentration, which is a powerful stimulus to feeding. The apparently reciprocal activities of the LHA and VMH are reiterated in the context of glucose-sensing: the VMH is rich in glucoseresponsive neurons (GRN), which respond to an increase in blood glucose levels and may help to terminate feeding (7). The DMH, located immediately above the VMH, contains abundant insulin and leptin (Ob-Rb) receptors. ARC NPY/AGRP neurons also terminate here. The DMH has extensive connections with other hypothalamic nuclei; it and the PVN are thought to integrate opposing signals from the VMH and LHA, effectively acting as a functional unit that initiates, maintains, and ultimately terminates feeding (8). The structure of the human hypothalamus is broadly similar to that in the rat. Although details of the neuronal circuitry have not been reported, the distributions of major neuropeptides such as NPY, POMC, and Orexin A appear to conform with those in rodents. MEDULLARY AREAS The regulation of energy homeostasis also involves multiple brain regions outside the hypothalamus. The medulla contains the nucleus tractus solitarius (NTS), which 48 HUNGER AND SATIETY: A VIEW FROM THE BRAIN receives sensory inputs from the viscera and relays these to the hypothalamus. These visceral signals carried by sensory (afferent) fibers of the vagus nerve include gastric distension and portal-vein glucose levels, and thus describe nutritional state as viewed by the gut. The intestinal peptide cholecystokinin (CCK), which is released by the gut and is involved in meal termination, also signals to the NTS via receptors (CCKA) on sensory terminals of the vagal nerve. Taste is another sensory modality conveyed to the NTS. Some NTS neurons are glucose-receptive; others express POMC and the melanocortin-4 receptors (MC4-R) that are the target for the POMC product, a-melanocytestimulating hormone (a-msh); administration of MC4-R agonists and antagonists into the fourth ventricle (adjacent to the NTS) affects feeding responses in the same way as when injected into the hypothalamus. Leptin receptors are also expressed, and the NTS-like the ARC and ME-lies 'outside' the BBB and is accessible to circulating signaling molecules such as leptin. Destruction of the NTS leads to overconsumption of palatable food, confirming that the NTS and hypothalamus both play important roles in energy homeostasis. HYPOTHALAMIC PATHWAYS AND NEUROTRANSMTTTERS The hypothalamus contains a wealth of neurotransmitters and peptides to date, over 50 have been reported. They include the monoamines (serotonin, noradrenaline, adrenaline, dopamine), acetylcholine, and other classical neurotransmitters, together with an ever-expanding list of peptides. Many can influence feeding behavior and energy metabolism under experimental conditions in rodents. Some of the more convincing candidates will be discussed. Most of these neurotransmitters have been identified within the human hypothalamus, but relatively little is known of their neuronal pathways, sites of release, or possible functions in humans. Neuropeptide Y NPY, a 36-amino acid neurotransmitter belonging to the pancreatic polypeptide family, is one of the most abundant and widely distributed neurotransmitters in the mammalian central nervous system, including that of man. NPY concentrations are particularly high in the hypothalamus, mostly derived from neurons in the ARC (Fig. 1), 90% of which also express AGRP (9). The bulk of ARC NPY neurons project to the PVN and DMH, which also receive inputs from NPY-containing fibers ascending from adrenergic nuclei in the medulla. There are also short projections that terminate within the ARC itself; NPY is thought to inhibit POMC neurons (via Yl receptors) and may also inhibit the NPY neurons themselves via Y2 receptors (10) (Fig. 2). NPY injected into cerebral ventricles or directly into the PVN, DMH, or LHA, induces pronounced hyperphagia indeed, NPY is one of the most potent central appetite stimulants known. It also reduces thermogenesis, through inhibition of the HUNGER AND SATIETY: A VIEW FROM THE BRAIN 49 FIG. 2. Interactions between pro-opiomelanocortin and neuropeptide Y neuronal projections within the hypothalamus sympathetic outflow to brown adipose tissue and other thermogenic tissues. Chronic NPY administration induces obesity, which mimics the features of genetically obese rodents (ob/ob and db/db mice and the phenotypically similar fa/fa Zucker rat); as will be discussed, this resemblance is more than mere coincidence because overactivity of the ARC NPY neurons is thought to contribute to hyperphagia, reduced thermogenesis, and adiposity in these mutants. The orexigenic action of NPY is thought to be mediated by specific subtypes of NPY receptors, probably Y5, with Yl likely to play an additional role (11). ARC NPY neurons become overactive in animals that have lost body weight and fat through energy deficits, such as in starvation, lactation, or insulin-deficient diabetes. NPY expression is increased, and elevated NPY release has been confirmed directly by stereotactic sampling in the PVN of starved and diabetic animals (12). The NPY neurons may be stimulated under these circumstances by decreases in circulating levels of insulin or leptin, which both inhibit NPY gene expression in the ARC (13), or by the increase in corticosterone concentration, which is stimulatory; the ARC NPY neurons express both Ob-Rb leptin receptors and glucocorticoid 50 HUNGER AND SATIETY: A VIEW FROM THE BRAIN receptors. ARC NPY neurons are also overactive in rodents with genetic obesity that is due either to leptin receptor defects (e.g., caused by db/db and fa/fa mutations in the mouse and rat, respectively) or to loss of biologically active leptin (ob/ob mouse). This disinhibition implies that leptin is normally a crucial regulator of the ARC NPY neurons. However, NPY does not appear to mediate overeating under all conditions, nor in all forms of obesity. ARC NPY neuronal activity is reduced in rats with dietary obesity induced by voluntary overeating of a palatable diet; the neurons may be inhibited in an attempt to limit overeating and weight gain, possibly in response to the increase in plasma leptin that occurs during the development of dietary obesity (14). Surprisingly, transgenic 'knockout' mice that lack NPY eat and grow normally (15). In our view, this does not rule out a role for the NPY system in regulating food intake, but instead highlights the potential for other neuronal systems or transmitters to take over from NPY a general caveat when using the knockout approach to explore the control of energy homeostasis. It has recently been shown that AGRP messenger mrna and immunoreactivity are upregulated with fasting in NPY knockout mice, suggesting that AGRP (also produced by the NPY neurons) may compensate for the lack of NPY in this model (16). Overall, the ARC NPY neurons appear to serve a protective, anti-starvation function, acting to correct the effects of prolonged periods of inadequate food supply by increasing the drive to locate and consume food, while limiting energy expenditure to prevent further depletion of body energy stores. Melanocyte-Stimulating Hormones The melanocortin neurons produce various peptides derived from a common precursor, POMC. Of these, a-melanocyte-stimulating hormone (a-msh) inhibits feeding when injected centrally and is considered to be the most important melanocortin regulator of feeding; 3-MSH may also play a similar role. POMC is synthesized in specific neurons of the ARC and NTS, and discrete a-msh-containing pathways project from the ARC to many brain regions, particularly elsewhere in the hypothalamus. Three melanocortin receptor subtypes, MC3-R, MC4-R, and MC5-R, have been located in the brain; both MC3-R and MC4-R are expressed within specific hypothalamic nuclei, including the VMH, DMH, and ARC-ME (17,18). The activity of the melanocortin system interaction can be modulated by endogenous antagonists, as well as the agonist, a-msh. The first to be discovered was a 131-amino acid peptide termed agouti, responsible for the striking phenotype of the obese yellow (AY) mouse, a long-recognized rodent model of obesity. The cause is a mutation in the promoter region of the agouti gene, which results in ectopic expression of agouti peptide in numerous sites, including the hypothalamus; here, antagonism of MC3-R and MC4-R leads to hyperphagia, reduced energy expenditure, and ultimately obesity (19). Thus, it was suggested that a-msh acts tonically via the hypothalamic melanocortin receptors, to restrain food intake and body mass; HUNGER AND SATIETY: A VIEW FROM THE BRAIN 51 under normal physiologic conditions, this system is held in check by another melanocortin antagonist, AGRP, as will be discussed. Both MC3-R and MC4-R probably mediate the hypophagic effects of the melanocortins, but recent studies have given MC4-R a central role. MC4-R knockout mice display obesity similar to that of the A Y mouse (20). Additionally, powerful modulators of feeding are more selective for MC4-R than MC3-R while an MC3-R preferring agonist, -y-msh, has little effect on food intake (21). Furthermore, MC4-R in key appetite-regulating hypothalamic nuclei have been shown to be selectively regulated in rats subjected to altered nutritional state (underfeeding or overfeeding), while the density of MC3-R does not change in these conditions (18). On the other hand, the MC3-R knockout mouse becomes obese; adiposity develops despite reduced food intake, apparently because of greater feeding efficiency, while mice lacking both MC3-R and MC4-R demonstrate greater obesity than that of MC4-R deficiency alone (22). Thus, both these melanocortin receptors probably participate in the regulation of body weight. The melanocortin system responds to various peripheral signals of nutritional status, notably leptin. Approximately 30% of ARC POMC neurons express the Ob- Rb isoform of the leptin receptor, and intraperitoneal leptin administration increases hypothalamic POMC mrna levels, while conditions associated with decreased leptin (e.g., fasting) or mutations that cause loss of the leptin signal (ob/ob and fa/fa/) show decreased POMC mrna levels (23). Leptin therefore appears to stimulate POMC neurons, consistent with the observation that both inhibit feeding. There is also evidence that leptin may act on a particular subset of neurons (either POMC or NPY/AGRP) that project specifically to MC4-R in the VMH and so determine an individual rat's susceptibility to dietary-induced obesity (24); through this interaction, a relative increase in leptin soon after exposure to a palatable diet may somehow 'program' this pathway to resist overeating in the longer term. A unique feature of the melanocortin system is the presence of the endogenous antagonist, AGRP. AGRP expression is limited to the NPY neurons of the ARC, but it is thought to be released into the same synaptic complex as a-msh in some hypothalamic nuclei. AGRP injected centrally (or overexpressed in transgenic mice) causes marked and prolonged hyperphagia food intake may be stimulated for several days after a single injection and this can override leptin-induced inhibition of feeding (25). Interestingly, AGRP may be regulated more robustly by altered metabolic status than the melanocortins themselves because changes in AGRP concentrations are observed in dietary-obese and food-restricted animals in the absence of any alterations in a-msh or POMC (26). This suggests that AGRP may finetune the activity of the melanocortin axis and thus its tonic restraining effect on food intake and body weight. Recent evidence indicates that AGRP may stimulate feeding through an additional mechanism that is independent of its antagonism of melanocortin receptors (27). AGRP expression is increased in ob/ob and db/db mice, and probably contributes to hyperphagia in these models. The melanocortin and NPY neuronal systems of the ARC apparently interact with each other in a reciprocal fashion. MC4-R knockout mice respond to the orexigenic 52 HUNGER AND SATIETY: A VIEW FROM THE BRAIN effects of NPY, and the NPY Yl selective antagonist BW1229U91 significantly attenuates the feeding effects of the MC4-R antagonist HS014 (28). MC3-R are expressed by NPY neurons and there is evidence that melanocortinergic neurons exert inhibitory control over the NPY neurons (see Fig. 2). Thus, stimulation of the ARC NPY neurons could enhance feeding through a dual action, with activation of NPY receptors and also antagonism of MC4-R by release of AGRP. Additionally, the ARC POMC neurons express Yl receptors and receive inhibitory inputs from NPY terminals (29). Thus, NPY release could potentially inhibit the ARC melanocortin system directly at the cell body as well as postsynaptically through AGRP release. Cocaine- and amphetamine-regulated transcript (CART) was first identified as a major brain mrna species that was upregulated by cocaine and amphetamine (30). The CART protein is coexpressed with POMC neurons of the ARC and is an appetiteinhibiting factor that is upregulated by leptin; it may function as an anorectic neuropeptide in the regulation of food intake. However, in contrast to the marked obesity seen with knockout or mutations affecting MC4-R, POMC, or leptin, knockout of CART only predisposes mice to become obese when eating an energy-dense diet (30). Overall, CART may act synergistically with the melanocortin axis to restrain feeding. The melanocortin axis operates in humans, as confirmed by recent observations that rare cases of morbid ob
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