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• W181372405 abstract "That body weight is regulated has been evident to physiologists for many years. When access to food is restricted, animals increase their desire for food and indulge heartily when food reappears. To conserve energy during caloric restriction, appetite is regulated and the overall metabolic rate declines. Conversely, to resist obesity, forced overfeeding suppresses appetite and increases metabolic rate. As tiny surgical or chemical lesions within the hypothalamus can produce obesity or leanness by disrupting the link between appetite and metabolic rate, it had been surmised that the hypothalamus played a key integrative role in energy balance, as it does for many other homeostatic processes. Physiological control of energy balance, is obviously imperfect, as judged by the high prevalence of obesity in the modern world. Until recently, none of the molecular elements of energy homeostasis had been identified. But as several genetic syndromes featuring severe obesity have been identified in mice, and these syndromes are typically characterized by both increased appetite and decreased energy expenditure, a genetic approach should eventually identify critical control points for energy homeostasis. The results of the past five years have, however, exceeded all expectations, and the clear outlines of a carefully balanced regulatory system are now evident. Energy homeostasis is governed by three distinct, but integrated factors: appetite, energy expenditure and linked endocrine/metabolic pathways. The control of appetite requires several physiological inputs to the central nervous system (CNS), and most critically to the hypothalamus. These include a means of monitoring the levels of neural and endocrine messages from the gut signaling recent food ingestion, the levels of various molecules in the blood, such as glucose, and the levels of a previously elusive signal reflecting the overall state of energy stores. This signal is known to be leptin, the product of the ob gene. Cultural and psychological factors should not be ignored as important inputs to appetite control, but these are difficult to integrate into an understanding of the molecular basis of energy homeostasis. The regulation of energy expenditure for all the energy-requiring processes in the body is complex. Two particular elements of this regulation are tightly controlled: the first is the key role that thyroid hormone activity has in the regulation of metabolic rate; the second is the system for altering the state of ‘mitochondrial uncoupling'— the tightness with which substrate oxidation is linked to ATP formation. In uncoupled mitochondria, substrate oxidation proceeds without ATP formation, the net result being production of heat, rather than storage of energy as ATP Regulated mitochondrial uncoupling occurs either in brown adipose tissue, which expresses uncoupling protein 1, or elsewhere in the body, through the actions of the recently identified uncoupling proteins 2 and 3. Thyroid hormone may regulate metabolic rate in part by affecting expression of uncoupling proteins. The brain controls the thyroid axis through the neuropeptide thyrotropin releasing hormone (TRH), and influences mitochondrial uncoupling through the autonomic nervous system, which innervates brown adipose tissue. Long-term energy homeostasis requires that energy needs are linked to the disposition of metabolic fuels — which is orchestrated mainly by insulin — and to neuroendocrine function, including the control of reproduction, which is actively suppressed during periods of energy deficit. So how do these disparate systems work in concert to maintain homeostasis? A fundamental component of the regulatory system is the hormone leptin. This 16 kDa peptide is a member of the cytokine gene family and is expressed predominantly in adipose cells. Its expression rises as energy stores increase and falls rapidly during periods of starvation. An absence of leptin results in severe obesity that begins shortly after birth in both rodents and humans; postnatal leptin replacement reverses the disorder. Leptin deficiency also results in numerous other defects in endocrine function and in insulin insensitivity. The leptin receptor is a member of the class I cytokine receptor family and, in common with these receptors, signals through the JAK/STAT pathway. JAK is a non-transmembrane tyrosine kinase that associates with the leptin receptor and is activated after the receptor binds ligand. JAK then phosphorylates STAT transcription factors, which dimerize and move to the nucleus where they regulate gene transcription. A mutation affecting the structure of the leptin receptor causes obesity that is refractory to leptin therapy. Taken together, these properties suggest that leptin controls an important metabolic switch. Leptin acts primarily within the brain, and particularly in the hypothalamus. The end result of normal leptin activity can, in many cases, be mimicked by the administration of tiny quantities of leptin directly within the CNS, at levels that cannot be detected in the peripheral circulation. Although present in several locations inside and outside the CNS, the signaling form of the leptin receptor is expressed abundantly in several discrete cell groups within the hypothalamus that have previously been associated with regulation of energy homeostasis. These include the arcuate nucleus, the ventromedial nucleus and the dorsomedial nucleus. Leptin administered into the bloodstream affects the function of these neurons. It has long been known that many neuropeptides, including those expressed within the hypothalamus, influence food intake and/or energy expenditure after being injected into the brain. An important member of this family of molecules is neuropeptide Y (NPY), which is widely expressed in the CNS, including the arcuate nucleus of the hypothalamus. NPY potently induces rodents to eat, suppresses energy expenditure through its effects on the autonomic nervous system, and can cause obesity with prolonged administration. Expression of NPY in the arcuate nucleus rises during starvation, as expected for a molecule that promotes feeding, and this increase is related in part to the relaxation of the inhibitory effect of leptin on the NPY neurons when leptin levels fall during starvation. Although leptin-deficient mice crossbred with NPY knockouts are somewhat less obese, their obesity is still severe, and mice lacking NPY have no obvious phenotype related to energy homeostasis. Thus, there must be other critical leptin targets, in addition to the NPY neurons. Tissue-specific processing of the proopiomelanocortin (P0MG) molecule — which gives rise to peptide hormones including adrenocorticotrophic hormone, β-endorphin and α-melanocyte stimulating hormone (α-MSH) —has only recently been viewed as being involved in energy balance. There are five melanocortin receptors, all of which are members of the G-protein coupled receptor family. Knockout of the melanocortin 4 receptor (MC4R; expressed primarily in the CNS and especially in the hypothalamus) by means of mutations in mice and in humans, results in obesity. The obesity is less severe than that produced by leptin deficiency or resistance, and some of the endocrine features are absent, suggesting that this pathway mediates an important part, but not all, of the leptin signalling process. Two antagonistic ligands, each of which is directly regulated by leptin within the arcuate nucleus of the hypothalamus, converge on the MC4R receptor (see Figure 1). The agonist is α-MSH, produced in the POMC neurons in the arcuate nucleus, which in turn are positively regulated by leptin. Synthetic antagonists of MC4R block many of the appetite-suppressing effects of leptin. Deletion of the POMC gene not only causes obesity in mice and humans but also results in disturbances because of the loss of other POMC peptides. The natural MC4R antagonist is agouti-related peptide (AgRP). Its expression in distinct arcuate neurons is potently inhibited by leptin. Administration of AgRP to the brain promotes food intake, and transgenic expression of this peptide promotes obesity. Thus, as leptin levels rise in the transition from the starved to the fed state, leptin acts in the hypothalamus to induce expression of α-MSH, the inhibitor of food intake, and inhibit expression of AgRP, the stimulator of food intake, both of which act through a common receptor (see Figure 1). Other important central pathways and mediators affect energy homeostasis. Among these is the cocaine and amphetamine related transcript (CART), which is coexpressed with POMC in arcuate neurons and also inhibits food intake. Melanin concentrating hormone (MCH) is expressed in the lateral hypothalamus, a region that in the 1940s was dubbed the ‘feeding center’ because lesions in this region resulted in loss of appetite. MCH was first identified as a potential mediator of appetite when its mRNA was found to be present at increased levels in hypothalami of genetically obese mice, and to induce feeding after injection into the brain. Mice lacking the MCH gene are lean and hypophagic (they eat less). There is some evidence that the MCH neurons have a physical connection to NPY/AgRP and POMC/CART neurons in the arcuate nucleus, a finding that begins to enable a sketch to be made of the architecture of the hypothalamic pathways underlying leptin action (see Figure 1). Although recent progress in understanding the regulation of energy homeostasis has been extraordinary, the metabolic pathways have yet to be fully identified. The identity of the initial hypothalamic circuit for leptin regulation of appetite does not yet provide us with a full understanding of what hunger really represents to a mouse or a human being. We don't know how a hypothalamic neural circuit can change our conscious awareness of a desire to eat, nor how this pathway could relate to our habits and our neuroses. Nor do we know how olfaction and visual cues tie in to these pathways to influence hunger, as we all know that they do. How diverse are the pathways involving leptin activity on appetite, compared with its effects on energy expenditure and endocrine function? Are there distinct subcircuits for each type of activity? Initial evidence suggests that this may be so but the story is vague at present. Are there other important hormonal pathways that act in concert with leptin? Glucocorticoids and sex steroids modify body weight and affect leptin levels, but a detailed understanding of how these signals are integrated awaits further work. Insulin is another interesting participant in energy homeostasis. Some evidence supports the idea that insulin, in addition to its classic metabolic role, affects the hypothalamus, although less potently than leptin. Perhaps insulin has a role as a positive regulator of leptin expression (see Figure 1). The final conundrum relates to leptin resistance, which seems to underlie the proclivity of humans and many strains of mice to become obese when food supplies are abundant and the need to expend energy is limited. In these situations, leptin concentrations rise to a level that should result in leanness but, paradoxically, this is not the outcome and we do not know why. Current work on leptin resistance is concentrating on the possibility that the access of leptin to its sites of action in the CNS is blocked somehow, and/or that there are defects in leptin signal transduction in responsive neurons. Whatever the mechanism, leptin resistance seems to reflect an evolutionary imperative to allow energy storage to take place at times of abundance. Hence, leptin should be viewed as a switch between the fed and the starved states, and not as a regulator of obesity. The discovery of leptin and some of its biochemical and cellular targets in the hypothalamus establish a new context for considering the regulation of energy homeostasis and body weight. The really big questions that remain unanswered involve the identification of the neural circuits through which the leptin signal is integrated with other critical information relevant to homeostasis, and the details of the efferent pathways through which the brain controls both metabolism in the peripheral tissues and the awareness of hunger within the brain. These questions are certain to be vigorously explored over the next several years. Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS: Role of leptin in the neuroendocrine response to fasting.Nature 1996, 382:250-252. Elmquist JK, Elias C, Saper GB: From lesions to leptin: Hypothalamic control of food Intake and body weightNeuron 1999, 22:1-20. Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD: Role of melanocortinerglc neurons in feeding and the agouti obesity syndrome.Nature 1992 385:165-166. Fleury C, et al.: Upcoupllng protein-2: a novel gene linked to obesity and hyperinsullnemia.Nat Genet 1997, 15:269~272. Halaas J, Gajiwala K, Maffei M, Cohen SL, Chart BT, Rabinowitz D, Lailone RL, Burley SK, Friedman JM: Weight reducing effect of the plasma protein encoded by the obese gene.Science 1995, 269:543-546." @default.
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