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| NEUROENDOCRINE INTEGRATION OF
BODY WEIGHT REGULATION Chapter 5 - Matthias Tschöp, M.D., and Tamas L. Horvath, DVM, Ph.D. May 28, 2003 TO OBTAIN A DOWNLOAD OF THIS CHAPTER IN WORD OR PDF FORMAT, CLICK HERE |
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| NEUROENDOCRINE INTEGRATION OF
BODY WEIGHT REGULATION Chapter 5 - Matthias Tschöp, M.D., and Tamas L. Horvath, DVM, Ph.D. May 28, 2003 TO OBTAIN A DOWNLOAD OF THIS CHAPTER IN WORD OR PDF FORMAT, CLICK HERE |
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INTRODUCTION For more than 70 years, increasingly sophisticated methods have been brought to bear on the problem of the brain involvement in the physiology of energy homeostasis and the pathogenesis of obesity. A vast number of experimental observations have been produced and, particularly within the last decade, the combination of novel genetic and sophisticated physiology techniques has allowed for great progress. These methods have helped identify metabolic hormones and their relationship to key peptidergic systems in the hypothalamus. Although the central integration of afferent signals reflecting acute and chronic energy requirements has started to become clearer, the neuronal pathways that actually initiate changes in ingestive behavior or energy expenditure are still largely unknown. Furthermore, researchers are far from understanding the overall picture of central body weight regulation that involves multiple brain areas outside the hypothalamus. This chapter summarizes the current knowledge and understanding of central nervous system anatomy and physiology in relation to mechanisms controlling energy balance. As in all mechanisms that control physiological processes, the brain plays a critical role in the regulation of energy homeostasis. Central nervous circuits instantly assess and integrate peripheral metabolic, endocrine and neuronal signals, and coordinate a response that modulates both behavioral patterns and peripheral metabolism according to acute and chronic requirements (1). Afferent signals. There are two main types of afferent inputs to the brain from peripheral organs that are relevant to energy homeostasis: hormones and neurons (2). Endocrine signals that reflect the metabolic state arise from different peripheral sites such as the thyroid, adrenals, muscle, fat, reproductive tissue and gastrointestinal organs (3,4). These hormones are secreted in response to current conditions regarding metabolic state and energy homeostasis, and convey information to the respective specific areas in the brain. Among the more relevant of these signals is the gastrointestinal hormone, cholecystokinin (CCK), which was first discovered in 1973. Peripherally released CCK acts centrally and initiates an acute (but not chronic) negative energy balance via pathways predominantly localized in the brainstem. CCK is thought to play a physiological role in regulating meal termination and it was long mistaken as the crucial missing factor in the most obese rodent known to man: the ob\ob mouse (5). The ob\ob-mouse phenotype results from a spontaneous mutation, that long before its identification, was already speculated to be caused by the lack of a peripheral signal that informs the brain about existing energy stores (6). Although the molecular technology was lacking to isolate the responsible gene or its product, brilliant physiological parabiosis experiments connecting the circulation of ob\ob mice with that of their genetically normal littermates yielded the proof of this concept (6). Positional cloning of the ob-gene finally led to the discovery of the proteohormone, leptin, which is predominantly produced by fat cells (7). Leptin is expressed according to the size of fat stores and its administration induces a negative energy balance mediated by neuronal structures in the hypothalamus and the brainstem. The role of leptin in signaling the brain about chronic changes in energy status is completed by insulin, which conveys additional information about long-term changes of peripheral metabolism to the brain. Centrally administered insulin triggers a negative energy balance, while neuron-specific deletion of its receptor causes obesity (8). Along with these signals, which most likely contribute to the regulation of chronic energy balance, hormones reflecting caloric intake and acute nutritional requirements complete the information flow to the brain. One of these factors, PYY(3-36), a gut hormone that is secreted in response to ingestion of food and is thought to specifically act via hypothalamic Y2 receptors, acutely induces a negative energy balance (9). The only known peripheral hormone with orexigenic action, the gastro-enteric peptide ghrelin, apparently counterbalances energy homeostasis in opposition to the multiple anorectic signals described above (10). Ghrelin, which predominantly targets the same neuronal structures on which leptin and PYY(3-36) exert their action, even induces a positive energy balance resulting in increased adiposity. Since ghrelin is secreted in response to caloric restriction and its expression and secretion are rapidly suppressed by food intake, it has been proposed to play a physiological role in meal initiation as the endogenous "hunger hormone" (11). Additional gastrointestinal hormones have been identified as afferent signals involved in energy balance regulation, but either their exact mechanism of action is not yet understood or their physiological role is still unclear. Intestinal glucagon-like-peptide 1 (GLP-1) decreases appetite and food intake in rodents, but dependent of the doses used, GLP-induced taste aversion might be one of the mechanisms leading to a negative energy balance (12). Deletion of receptors for glucose-dependant insulinotropic polypeptide (GIP) protects against obesity, while the fat-cell and muscle-derived interleukin 6 (IL-6) is a cytokine that centrally induces a negative energy balance (13). Although classic hormones secreted by the endocrine glands are largely neglected as afferent signals that convey peripheral metabolic states, energy stores or nutritional requirements to the brain, they play an important role in the complex networks governing appetite and body weight (14). Central administration of corticosteroids, for example, induces appetite and increases fat mass (15). While the negative energy balance induced by thyroid hormones is mainly attributed to their multiple peripheral effects, T4 as well as T3 receptors are also localized in the brain, where they serve as important feedback targets (16). The same feedback principle exists for hormones of the somatotropic axis such as growth hormone and IGF-I (14). Apart from these and other hormones, essential metabolic substrates add to the integrated signal emerging from the periphery: glucose and free fatty acids directly inform centrally located sensors about the current state of carbohydrate and lipid metabolism (17). In addition to circulating signals, a parallel neuronal network also provides information about energy homeostasis to the brain. Satiety information generated during the course of a meal is largely conveyed to the brainstem by means of afferent fibers of the vagus nerve and by afferents passing from the spinal cord from the upper gastrointestinal tract. This information mainly converges in the nucleus tractus solitarius (NTS), an area in the caudal brainstem that integrates sensory information from the gastrointestinal tract and abdominal viscera, as well as taste information from the oral cavity. (2,18) Also see http://www.endotext.org/obesity/obesity3/obesityframe3.htm for more details. Efferent signals Coinciding with the integration of the multiple afferent signals that converge upon central circuits that regulate energy balance, these neuroendocrine networks simultaneously coordinate an appropriate efferent response. While it is evident that these efferent signals, such as hormonal, behavioral and neuronal outputs, induce changes in energy expenditure, it is still unclear how appetite induction is triggered by hypothalamic circuits involving the arcuate nucleus and other centers of feeding control such as the lateral hypothalamus. The classical endocrine axes consisting of hypothalamic releasing hormones, pituitary hormones and peripheral endocrine signals are, without exception, involved in maintaining the balance of metabolism and energy homeostasis. Activation of the Hypothalamic-Pituitary-Adrenal (HPA) axis induces a positive energy balance, while stimulation of the hypothalamic-pituitary-thyroid (HPT) axis produces energy deficits via an increased metabolic rate and the growth hormone (GH)-insulin-like-growth factor I (IGF-I) axis (also somatotropic axis) promotes lipolysis and muscle growth. Stimulation of the hypothalamic-pituitary-sex hormone axis (gonadotropic axis) causes a negative energy balance in women and an increased ratio of muscle:fat tissue in men. However, both the parasympathetic and the sympathetic nervous system are believed to represent the predominant mediating pathways from the brain to the periphery in the adjustment of energy balance according to acute and chronic requirements. (2,19) See also http://www.endotext.org/obesity/obesity4/obesityframe4.htm for more detailed information. Recent research into factors regulating appetite and adiposity has identified many new signals that play specific roles in the regulation of energy homeostasis. Many of these factors converge upon specific circuits in the central nervous system. These afferent signals from peripheral organs such as the stomach, fat stores or pancreas as well as the efferent pathways by which the brain regulates energy balance (in particular adipocyte function) include hormones as well as metabolites and neuronal structures. These recently discovered neuroendocrine networks are essential since a functional central control of energy homeostasis is dependent upon a rapid, reliable and effective communication between the brain and peripheral organs. THE NEUROANATOMY OF THE CENTRAL REGULATION OF ENERGY HOMEOSTASIS Information processing is via neurons in the brain. The signal flow within the brain that underlies metabolism regulation is a highly complex process and is based on neuronal interactions. The main information processing units of the brain are the neurons. Neurons are cells of ectodermal origin that have subcellular compartments specialized in receiving (dendrites and perikaryon) and forwarding (axons) information. Neurons interact with each other by synapses that are established between axon terminals and dendritic or perikaryal membranes. The information moves from axon terminal to the dendritic or perikaryal membranes. Synaptic transmission occurs either electrically, chemically via release of neurotransmitters or (neuro)modulators from synaptic vesicles of the axon terminal or by release of gaseous substances such as nitric oxide or carbon monoxide. In most cases, synaptic transmission can occur by all three means, although one may predominate depending on the action potential as well as on substances that may directly signal to the axon terminal from the extracellular space (such as other neuromodulators released by nearby axons or available by volume transmission, extra-cellular anion and cation concentrations as well as substances released to the extra-cellular space by paracrine or endocrine processes). The specificity of signal transduction is ensured by the appropriate connectivity within a given network and by the availability of receptors at the right sites for released neurotransmitters/modulators or peripheral metabolic hormones. While emerging data clearly suggest that glial cells also play a pivotal role in allowing normal neuronal activity, it is not unreasonable that interplay between neurons holds the key to understanding metabolism regulation. To this end, it is critical that the principles of neuronal physiology are mastered (beyond the short references provided here) to the deepest possible extent. Otherwise, attempts to decipher the role of the brain in obesity will remain elusive. Brain areas involved in metabolism regulation. There has always been a trend to simplify the regional contribution of brain areas to homeostatic regulation which has explicit advantages both from a theoretical as well as a practical perspective: it allows a relatively easy conceptualization of the involvement of brain mechanisms in the regulation of energy metabolism and has also contributed to a very rapid advancement of knowledge on the involvement of particular neuropeptides and their receptors in these processes (see below). On the other hand, the sharp focus on the hypothalamus, the arcuate nucleus in particular, also holds an inherent danger and that is the potential to not see the forest through the trees. It is important to remember that despite ever increasing data gathered in the last century, including the discovery of leptin (in 1994) and the repeated revelations of "the most important" hormone or neuropeptide, an effective pharmacotherapy for obesity is still lacking. Thus, when considering the brain structures discussed below and their putative function, the reader is advised to keep in mind that this is a reflection of our current understanding and not necessarily a rigid blueprint of metabolic regulation. Our present knowledge of these circuits continues to improve, but is far less clear than the pathways for vision, hearing or basic motor functions that, for example, involve and require interaction between the cortex, basal ganglia, striatum and cerebellum. Of the various brain areas, to date, the hypothalamus is considered the main integrator and processor of peripheral metabolic information (20-30). It should be noted, however, that arguably the brainstem plays an equal role in these processes (2,18). This basal diencephalic area of the brain contains several nuclei (i.e., collection of neuronal cells) that have been shown in the past century to be key brain regions in the regulation of homeostasis. Those hypothalamic nuclei that have been directly associated with metabolism regulation are (in antero-posterior direction) the paraventricular nucleus, arcuate nucleus, lateral hypothalamus-perifornical region, and the ventromedial- and dorsomedial hypothalamic nuclei (16, 31). Based on early degeneration studies, where specific brain areas were surgically or chemically destroyed to study their physiological function, these nuclei could be devided into two groups: one that promotes positive energy balance (lateral hypothalamus-perifornical area) and the other that promotes negative energy balance (ventromedial-, dorsomedial-, paraventricular nuclei). These nuclei are redundantly interconnected with each other, although, there is a predominance of efferent pathways that run in particular directions from one nucleus to another. For example, the arcuate nucleus, that is situated in the mediobasal aspect of the hypothalamus adjacent to the third ventricle, sends a large number of projections to the paraventricular- and dorsomedial nuclei, with less impressive projections to the lateral hypothalamus-perifornical region and with virtually no projections to the ventromedial nucleus. The ventromedial hypothalamus, on the other hand, projects to all of the aforementioned areas. The lateral hypothalamus-perifornical region projects massively to the arcuate, paraventricular and dorsomedial nuclei with little input to the ventromedial nucleus. The paraventricular nucleus has limited projections within the hypothalamus, but receives input from all of the other metabolism-related hypothalamic areas. One school of thought suggests that only the arcuate nucleus has the potential to receive most of the peripheral signals reflecting the metabolic state and that it houses parent cells of origin of two peptidergic systems (see below) considered as the primum movens of metabolism regulation. In support of a "primary sensory" function for the arcuate are the following facts. First, the arcuate nucleus is located most ventrally in the diencephalon where blood vessels bifurcate from the circle of Willis, and, this region is intimately associated with an area that is not protected by the blood-brain barrier; thus, metabolic hormones, such as leptin or ghrelin, may easily exert effects on arcuate nucleus neurons. From here, arcuate efferents relay information to target sites, such as the dorsomedial and paraventricular nuclei. While this is a tempting and likely scenario, to date, there is no conclusive evidence that the arcuate nucleus, itself, is not protected by the blood brain barrier or that other hypothalamic areas, such as the lateral hypothalamus-perifornical area, might not be targeted directly by peripheral hormones. Returning to the role of the arcuate nucleus as the primum movens of central regulatory mechanisms, the following should be considered: this region contains two key peptidergic systems, the neuropeptide Y (NPY)/agouti-related protein (AGRP)-producing cells and their counterpart, the pro-opiomelanocortin (POMC)-producing cells. The interplay between these two neuronal subpopulations (the so-called melanocortin signaling system; see below for further details) is believed to be essential to both food intake and energy expenditure regulation. However, destruction of the arcuate nucleus does not cause any drastic alteration in food intake or metabolism in general. While it can be argued that removing equal amounts of orexigenic promoter (NPY-AGRP system) and blocker (POMC) would result in "no change" overall, removal of the putatively essential sensor for afferent signals reflecting energy balance with these positive and negative charges should collapse the entire system. Further evidence undermining the necessity of the arcuate nucleus in feeding behavior are the findings that in the first 3 weeks of postnatal development of rats, the efferents of the arcuate nucleus peptide systems are not yet developed despite appropriate feeding behavior from the day of birth. It is also important to consider that because of the necessity of food injestion to sustain life, the systems examined here are likely to exhibit tremendous redundancy. If this is the case, then it is unreasonable to anticipate that a single "magic bullet" that targets one particular aspect of this system, will deliver long-term answers for obesity (26). Recently evolving studies indicate that both sensory and integrative functions are distributed across the basal forebrain as well as the caudal brainstem. A strong presence of leptin and insulin receptors, glucose-sensing mechanisms, and neuropeptide mediators in the brainstem suggests its pivotal role in coordinating energy balance regulation In addition, a physiological relevance is suggested by the demonstration that similar effects can be triggered independently by stimulation of respective forebrain and brainstem subpopulations of the same receptors (18). Furthermore, decerebrate and neurologically intact rats show similar responses to taste stimuli and are similarly sensitive to inhibitory feedback from the gastrointestinal tract, indicating that the caudal brainstem is sufficient to mediate ingestive responses. Also, hypothalamic-neuroendocrine responses to fasting depend on ascending pathways from the brainstem. This suggests that control mechanisms endemic to the hypothalamus and brainstem drive their unique effector systems on the basis of local interoceptive and visceral (in the case of the brainstem) afferent inputs and that a set of uni- and bidirectional interactions between these structures coordinates adaptive neuroendocrine, autonomic, and behavioral responses to changes in metabolic status (18). Of course, there are other brain areas besides the hypothalamus and brainstem that play important roles in feeding behavior. For example, it is critical that appropriate motor function is exerted in order to both gather food as well as to appropriately process ingested nutrients. Thus, both the motor cortex and mechanisms related to the motor system, including the interplay between the basal ganglia and substantia nigra dopamine cells, need to be considered. Similarly, motivational components of eating are also important elements of overall energy balance regulation and these are likely to be associated with neuronal processes in the nucleus accumbens (2). The debate over the neuronal blueprint of metabolism regulation is likely to continue and further scientific progress is needed to elucidate the brain circuitry governing energy balance to a point where useful therapeutic approaches become feasible. There are, however, concepts regarding other aspects of these regulatory processes that are much better understood at this point. These concepts involve the basic understanding of the importance of peptides and classical neurotransmitters in the central regulation of metabolism. Neurotransmitters and neuropeptides in hypothalamic circuits involved in metabolism regulation. The past decades have provided overwhelming evidence that the principle signaling modality within brain centers of energy balance regulation is via chemical synapses. As eluded to earlier, chemical neurotransmission occurs by the release of neurotransmitters and neuropeptides from synaptic vesicles of axon terminals onto their respective receptors located at the postsynaptic membrane or membranes of adjacent axon terminals. Studies indicate that the central regulation of feeding behavior and energy expenditure relies on the appropriate interaction between particular neuropeptides. In this regard, those key hypothalamic neuropeptide systems that have been most closely associated with metabolism regulation are summarized below. However, some other peptides that are involved to a lesser extent will not be discussed. A detailed and thorough description of these peptides and their functions can be found in elaborate reviews (1,2,16,18-31). NPY, a 36-amino acid peptide is one of the most abundant and widely distributed neuropeptides within the nervous system and is one of the most potent stimulators of feeding. NPY administered repeatedly into the hypothalamus induces obesity accompanied by hyperphagia, decreased thermogenesis in brown adipose tissue, hyperinsulinemia, hypercorticosteronemia, reduced plasma testosterone levels and insulin resistance in skeletal tissues. All of these adipogenic neuroendocrine and metabolic effects of central NPY administration persist when the NPY-induced hyperphagia is prevented by pair-feeding, demonstrating that hyperphagia is not the only mechanism by which central NPY increases adiposity. The levels of NPY mRNA in the arcuate nucleus respond to changes in energy status. For example, they are increased during fasting and chronically up-regulated in many rodent obesity syndromes, e.g., in the ob/ob mouse. At least 5 distinct receptors (Y1, Y2, Y4, Y5 & Y6), all belonging to the G-protein coupled receptor superfamily, mediate the actions of NPY. (9,16) AGRP is a neuropeptide produced in the arcuate nucleus NPY neurons. It is an endogenous ligand of melanocortin receptor subtypes, and upon binding to these receptors, it antagonizes (or acts as an inverse agonist upon) the effect of other ligands of these receptors, including a-melanocyte stimulating hormone (a-MSH). a-MSH is one of the most potent anorexigenic brain signals (see below for further details on this mechanism). (16, 25, 30) It has been known for a long time that opiates promote phagia. The single-copy POMC gene encodes the POMC precursor PP, which yields the opioid, ß-Endorphin (ß -END), and the non-opioid peptides, adrenocorticotropin homone (ACTH) and a-?MSH. Within the hypothalamus, POMC neurons, localized exclusively in the arcuate nucleus (ARC), innervate the paraventricular nucleus (PVN), dorsomedical nucleus (DMN), and other areas of the hypothalamus, where microinjection of ß-END and opiate agonists that bind to the m-receptor subtype stimulate feeding. Neurons producing the two pentapeptides, methionine-enkephalin (met-ENK) and leucine-enkephalin (leu-ENK), are more widely distributed in the hypothalamus, and discrete populations of leu-ENK or met-ENK-immunopositive perikarya have been visualized in sites relevant to feeding, such as the ARC, ventromedial nucleus (VMN), DMN, and PVN, sites that are also richly innervated by ENK-immunopositive fibers. Central injection of the third hypothalamic opioid, dynorphin A(1-17), derived from the precursor prodynorphin, stimulated feeding by activating the k-opiate receptor subtype. Dynorphin-producing cells are also found in various regions of the hypothalamus, including the ARC and PVN. A critical evaluation of food intake induced by various opioid compounds showed that opioid-evoked feeding is generally short lived and relatively modest . (18,32) The recent discovery of cannabinoid receptors and their endogenous ligands (endocannabinoids) within the central nervous system has lead to the inference that they are involved in the regulation of energy balance, suggesting that an endocannabinoid tone could play a key role in the neurochemical regulation of appetite. The effects of endocannabinoids on appetite may be explained by the expression of the ligands and their receptor (CB1) in the hypothalamus as well as in other feeding-associated brain regions like the limbic forebrain. These areas are thought to be mainly involved in reward processes that mediate, for instance, the value of food as an incentive. Acting in brain regions like the nucleus accumbens and the hippocampus, endocannabinoids may specifically drive appetite for palatable food. In addition, the interactions of the endocannabinoid system with other pathways, like the opioid system, may partially explain its involvement in reward processes. Moreover, the central levels of endocannabinoids are modified by acute peripheral energy balance changes and hypothalamic endocannabinoids are suppressed by leptin. Consistent with enhanced endocannabinoid signaling in the hypothalamus of mutant rodents with defective leptin signaling, blockade of CB1 leads to a decreased food intake in these animal models, strongly suggesting that the endocannabinoid system might play an important endogenous role in the hypothalamic regulation of energy homeostasis. Endocannabinoids have recently been classified as neuromodulators belonging to the family of the appetite-stimulating neuromediators. (33) A population of neurons in the zona incerta and lateral hypothalamus (LH) produce the 19-amino acid peptide, melanin-concentrating hormone (MCH), and project to several hypothalamic, limbic and cortical areas. Qu et al. reported potentiation of ongoing nocturnal feeding for 4-6 h by MCH administration at the onset of the dark phase. Further studies revealed several parallels between MCH and NPY systems in the hypothalamus. MCH augmented ongoing feeding; fasting stimulated MCH gene expression in the hypothalamus, and MCH mRNA was elevated in genetically obese ob/ob mice (). MCH also stimulated the hypothalamo-pituitary-adrenal axis. These similarities raised the intriguing possibility that MCH may be an additional orexigenic signal that either independently or, together with NPY, participates in the hypothalamic regulation of energy homeostasis. However, this assumption must await further experimental validation since potent anorectic effects on nighttime food intake and suppression of body weight by extremely low doses of MCH have been reported. Similarly, microinjection of MCH into the zona incerta-LH region reduced feeding. Orexigenic effects of MCH in rats have also been observed, but relative to NPY, MCH-induced feeding seems less impressive and of shorter duration. Further, despite the acute stimulatory effects of MCH, cumulative 24-h intake was unaffected, and repeated daily injections stimulated food intake for a few days without changing the body weight. Interestingly, small lesions in the VMN that stimulated MCH gene expression in the hypothalamus failed to evoke hyperphagia (16,34). Hypocretins 1 and 2 have been localized in clusters in the dorsal and lateral hypothalamic area and perifornical hypothalamus. Immunoreactive axons emanating from these cells innervated various forebrain structures anteriorly, such as the ARC, paraventricular nucleus of the thalamus, preoptic area and the septal nuclei, and caudally, the locus coeruleus and a few other sites in the brainstem. Intracerebroventricular injections of hypocretin 1 (orexin A) and hypocretin 2 (orexin B) stimulated feeding in a dose-related fashion with orexin A significantly more effective than orexin B, possibly due to activation of both orexin A and B receptor subtypes. Orexin was found to be less effective than NPY in stimulating food intake and, as with NPY and MCH, fasting up-regulated orexin gene expression in the hypothalamus. A comparative evaluation of the potency of orexins with other orexigenic signals examined thus far indicates that higher doses of orexins (given by intracerebroventricular injection) than of other substances (galanin, MCH, or gamma-aminobutyric acid) are needed to elicit significant stimulation of feeding. The extensive anatomical and experimental evidence clearly implies that orexigenic signals do not act one at a time, but rather, are an interconnected network that integrates the hypothalamic regulation of daily food intake. (16,35) The melanocortin system is thought to be one of the most significant pathways involved in the regulation of food intake, with mutations within the system found in approximately 4% of the cases of genetic obesity in humans. Melanocortins are peptides that are cleaved from the pro-opiomelanocortin (POMC) precursor molecule and exert their effects by binding to members of a family of melanocortin receptors (MC1-R to MC5-R). a-MSH, one of the products of the POMC gene, acts as an endogenous agonist of the MC3-R and MC4-R, the two melanocortin receptor subtypes that are thought to be important in the regulation of food intake. The importance of the melanocortin system in the control of food intake and energy regulation was first highlighted by the hyperphagic, obese and hyperinsulinemic phenotype of the agouti lethal yellow (Ay/a) mouse. Agouti is a 131 amino acid peptide, which is secreted by dermal papilla cells during the hair growth cycle, where it normally antagonizes a-MSH binding to the MC1-R in the melanocyte. This antagonism shifts pigment production from eumelanin to phaeomelanin resulting in a sub-apical yellow band. Ectopic expression of agouti in the Ay/a mouse results in a yellow coat color and obesity, the latter due to the agouti acting as an antagonist to a-MSH at the central MC4-R. Targeted gene deletion of the MC4-R results in a hyperphagic obese mouse similar in phenotype to the Ay/a mouse. The melanocortin system has an endogenous antagonist, agouti-related protein (AGRP), coexpressed in the same neuronal population as NPY. AGRP acts as an antagonist (or an inverse agonist) to increase food intake and decrease energy expenditure at the MC3-R and MC4-R. (36). Corticotropin-releasing hormone (CRH) family of peptides CRH was isolated and sequenced in 1981. It is the primary hypothalamic hormone that stimulates the release of pituitary ACTH, which stimulates corticosterone secretion from the adrenal glands. CRH-producing cells involved in regulation of the pituitary-adrenal axis are localized mainly in the parvicellular PVN. These neurons project to the external zone of the median eminence to release CRH into the hypophyseal portal system for transport to the pituitary. CRH also exerts powerful excitatory effects on arousal and locomotor activity and elicits "anxiogenic-like" effects in rats. Central injection of CRH produces anorexia, as evidenced by attenuation of nocturnal and fasting-induced feeding, and diminishes feeding in a number of pharmacological and behavioral paradigms designed to evaluate ingestive behavior. These diverse biological effects of CRH are exerted at specific sites in the brain. Indeed, multiple subpopulations of CRH-producing neurons, CRH-immunoreactive terminals, and high-affinity binding sites have been localized in various regions in the brain. Microinjection studies revealed that the sites of anorectic action of CRH lies within the PVN, possibly mediated by CRH R1 or CRH R2 receptor types. The fact that intraventricular injection or microinjection of CRH into the PVN, and not elsewhere in the hypothalamus, inhibited NPY-induced feeding further strengthened the notion that CRH, if released locally in the PVN, may tonically restrain the action of endogenous orexigenic signals. (37) Urocortin, a recently described member of the CRH family with 45% sequence homology to CRH, has been shown to be more potent than CRH in suppressing both the fasting induced and nocturnal feeding. Reduction of nocturnal feeding by urocortin was found to be due to a reduction in meal size and not frequency of meal bouts. This observation questions the physiological significance of this anorexic peptide in nocturnal feeding marked by a robust increase in both meal size and frequency. The topographies of urocortin and CRH-expressing cells in the rat brain are quite different and interesting. Urocortin-expressing cells are found in the Edinger-Westphal nucleus, the lateral superior olive, the LH and supraoptic nucleus (SON), but not in the PVN. The higher anorectic potency of urocortin has been attributed to a relatively higher affinity of urocortin for CRH R2 and its splice variant CRH R2a. Although urocortin immunoreactive nerve fibers innervate the lateral septum, VMH, and medial amygdaloid nucleus, urocortin microinjections into the VMN, but not into the PVN, inhibited feeding. (37) Neurotensin (NT), isolated and characterized in the early 1970s, inhibits spontaneous and norepinephrine-induced feeding in rats, and there is evidence that NT and dopamine act synergistically to inhibit feeding. The neuroanatomical mapping of NT pathways in the rat hypothalamus is consistent with the existence of anorexigenic pathways. Within the hypothalamus, NT-like immunopositive neurons exist in several distinct nuclei. Notable among these are subsets of NT-producing neurons in the ARC, PVN, and DMN. In addition, these and neighboring sites are richly innervated by NT-immunopositive fibers. Interestingly, recent studies showed that a subset of NT-positive neurons in the DMN project to both the parvicellular and magnocellular PVN, sites in which microinjection of NT inhibited spontaneous feeding. In addition, consistent with a reciprocal interaction between NPY and NT underlying hyperphagia in rodents, it has been reported that ob/ob mice exhibit decreased hypothalamic NT mRNA and peptide levels in association with enhanced NPY levels and gene expression. (38) Glucagon-like peptide-1 (GLP-1) (7-36) amide is processed from proglucagon in intestinal L cells, and it is considered to be a hormone related to the glucagon/secretin family of peptides. Like several other gastrointestinal peptides, GLP-1 has been found in various forebrain sites and in hypothalamic sites that correspond with GLP-1-binding sites in the ARC and PVN. Extensive hypothalamic innervation by GLP-1-immunoreactive fibers apparently emanates from a single population of non-catecholamine-producing neurons in the caudal portion of the nucleus of the Solitary tract. Intraventricular administration of GLP-1 inhibited food intake in fasted rats, a response blocked by the concurrent administration of exendin (9 -39), a GLP-1-receptor antagonist. A physiological role of GLP-1 as an anorectic or satiety factor was suggested by the observations that exendin stimulated feeding in satiated rats during the lights-on period, and daily injections of exendin augmented food intake and body weight. Evidence suggests that one of the sites of GLP-1 action may be the PVN where GLP-1-immunoreactive fibers terminate and where exendin blocked GLP-1-induced activation of c-FOS. The anorectic effects of GLP-1 may be mediated through NPY signaling because GLP-1 inhibited, and exendin (9 -39) augmented, NPY-induced feeding. Suppression of feeding by GLP-1 likely involves inhibition of postsynaptic signaling initiated by NPY in the PVN and not by suppression of NPY synthesis in the ARC. The fact that GLP-1 may be an endogenous anorectic signal was also indicated by the report that attenuation of feeding by GLP-1 was not due to conditioned taste aversion. (39) Cocaine and amphetamine-regulated transcript Cocaine and amphetamine-regulated transcript (CART) was localized in the rat brain and shown to be distributed in feeding-related sites in the hypothalamus. Intraventricular administration of CART inhibited nocturnal as well as fasting-induced feeding in mice and rats. An extensive series of investigations by two laboratories presented strong evidence to show that CART may be a physiologically relevant anorectic signal. This view is supported by the following evidence: 1) administration of antiserum against CART, to neutralize the anorectic impact, increased nighttime feeding; 2) CART mRNA was localized in the ARC, PVN, supraoptic nucleus, rostral part of the VMH, anterior paraventricular nucleus of the hypothalamus, and several other nuclei in the diencephalon. Fiber projections from these CART-producing cells were located in a large number of hypothalamic nuclei; 3) expression of CART mRNA in response to fasting decreased in the ARC and DMH in normal rats; 4) in genetically obese rodents, Zucker (fa/fa) rats and ob/ob mice, CART gene expression in the ARC and DMH was decreased relative to wild-type controls; 5) leptin administration to ob/ob mice, which lack leptin, increased CART mRNA in the ARC to the range seen in wild-type lean control mice. This response was associated with a decrease in food intake in the ob/ob mice; 6) interestingly, CART administration markedly inhibited the NPY-induced feeding in fasted and normal rats. Although these results suggested an inhibitory action of CART exerted at postsynaptic levels, immunocytochemical studies showed a close apposition of NPY-containing terminals with the perikarya of CART peptide-immunoreactive neurons in the parvicellular PVN, possibly representing an NPY-CART communication line. This observation is highly suggestive of a regulatory role of NPY on CART output, in a fashion similar to NPY-->GAL, NPY-->POMC, NPY-->orexin signaling. Thus, CART-containing neurons and their projections appear to represent one of the most powerful physiological anorexic signaling pathways. (12) With respect to the role of ghrelin in the regulation of energy homeostasis, the recent finding of its localization in the hypothalamus created interest comparable to its discovery in the stomach. A uniquely distributed hypothalamic group of mostly bipolar neurons has been identified as producing small amounts of ghrelin. These neurons are not co-localized with any known centrally expressed hormone or neuropeptide, but, intriguingly, they do project directly to several previously identified hypothalamic appetite control centers. Furthermore, ghrelin receptor expression and binding is localized in multiple hypothalamic areas that neighbor NPY, AGRP, POMC, GABA and other neuropeptides and neurotransmitters substantially involved in appetite control. Ghrelin expression is found in neurons situated close to, but not connected with, the previously mentioned neuropeptides. These neuroanatomical findings, complemented by electrophysiology studies, provided evidence for the existence of a central circuit regulating appetite that involves ghrelin as a key-modulator (40). This chapter attempts to provide an overview of the known physiological processes that occur in the brain to integrate and analyze a large variety of afferent signals reflecting energy requirements and that respond with the appropriate compensatory changes in appetite, metabolism and behavior. Immediate conditions instantly induce hormonal and neuronal messages from the periphery that communicate to distinct areas of the brain the need for regulatory changes in order to maintain energy balance. It is within these brain areas that not only sensations such as hunger and satiety are created, but also outgoing impulses for food seeking behavior, changes in locomotor activity or appropriate modulations of peripheral metabolic drive are triggered. The localization and precise action of these brain centers, as well as the exact mapping of their interactive signal transduction pathways, remain largely unknown despite great scientific progress in this field during the last decade. A finely tuned balance of action potentials, synaptic neurotransmitters, feedback loops and neuropeptide expression levels between regulatory centers in the brainstem, hypothalamic nuclei, basal ganglia, accumbens nucleus and even the cortex underlies the constant adjustments that take place. The redundant multiplicity of factors governing energy balance, that have been generated due to the evolutionary need to ensure sufficient caloric intake, is regarded as one reason for the continued failure to generate an effective pharmacotherapy for obesity.
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