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Model for the regulation of energy balance and adiposity by the central nervous system^1,2,3

	ABSTRACT

TOP ABSTRACT INTRODUCTION CENTRAL EFFECTOR PATHWAYS FOR... CANDIDATE ANABOLIC EFFECTOR... CATABOLIC CENTRAL EFFECTOR... ROLE OF THE AUTONOMIC... SHORT-TERM, MEAL-RELATED FACTORS LONG-TERM CONTROLLERS OF... GLUCOCORTICOID SIGNALING IN THE... CONCLUSIONS REFERENCES

 
In 1995, we described a new model for adiposity regulation. Since then, data regarding the biology of body weight regulation has accumulated at a remarkable rate and has both modified and strengthened our understanding of this homeostatic system. In this review we integrate new information into a revised model for further understanding this important regulatory process. Our model of energy homeostasis proposes that long-term adiposity-related signals such as insulin and leptin influence the neuronal activity of central effector pathways that serve as controllers of energy balance.

Key Words: Body weight • adipose tissue • food intake • insulin • leptin • neuropeptide Y • glucocorticoids • obesity • energy balance • central nervous system • homeostasis • central effector pathways • arcuate nucleus • paraventricular nucleus • review

	INTRODUCTION

TOP ABSTRACT INTRODUCTION CENTRAL EFFECTOR PATHWAYS FOR... CANDIDATE ANABOLIC EFFECTOR... CATABOLIC CENTRAL EFFECTOR... ROLE OF THE AUTONOMIC... SHORT-TERM, MEAL-RELATED FACTORS LONG-TERM CONTROLLERS OF... GLUCOCORTICOID SIGNALING IN THE... CONCLUSIONS REFERENCES

 
In 1995, we described a new model for adiposity regulation in a supplement to the Journal (1). We proposed that discrete neuronal circuits exist within the brain that, when activated, exert potent, unidirectional effects on energy balance. We hypothesized that these central effector pathways transduce afferent input from adiposity-related hormonal signals into changes in feeding behavior and energy balance. Through this mechanism, the central nervous system (CNS) response to afferent signals that control the size of individual meals was proposed to be adjusted in proportion to changes in body adiposity, resulting in the long-term stability of fat stores. The present article integrates new information into a revised model for understanding this important regulatory process (Figure 1).

View larger version (20K): [in this window] [in a new window]   FIGURE 1. Model for the regulation of energy balance and adiposity. Neural systems termed central effectors of energy balance represent major controllers of food intake and autonomic outflow that affect the storage and mobilization of energy. Anabolic effector pathways promote feeding and suppress energy expenditure, whereas catabolic effector pathways have the opposite effect. Short-term, situational, and meal-related signals originate from various internal sources [eg, cholecystokinin secretion from the gastrointestinal (GI) tract], from the environment (eg, food-related cues), and from higher centers (eg, emotional and cognitive factors). Although short-term signals are major determinants of the size and timing of individual meals, their effect on fat stores is limited by the long-term regulation of energy homeostasis. This is because long-term, adiposity-related signals such as insulin and leptin regulate the output of the central effector pathways and modulate the central nervous system response to short-term signals in proportion to the level of fat stores. In this way, changes in energy balance that alter fat stores elicit compensatory responses in central effector pathways that preserve energy homeostasis.

Food intake and energy expenditure are influenced over the short term by input from a wide variety of situational and meal-related factors. Within this broad category are physiologic signals, including neuronal information related to ongoing circadian rhythms, metabolic signals reflecting the rate of utilization of different fuels by brain and abdominal viscera, gastrointestinal signals resulting from gastric distention, and the release of peptides from the gastrointestinal tract in response to nutrient ingestion. Emotional factors and the palatability and nutrient content of available food are additional inputs that can exert strong, transient effects on the amount and type of food consumed from one meal to the next. Because short-term factors can arise unpredictably and can influence powerfully the size and frequency of meals, variability in daily patterns of energy intake is the rule. Moreover, because short-term, meal-related signals are not generated in proportion to energy requirements, daily food intake and energy expenditure are not closely correlated in humans (12).

The biological system that regulates body adiposity was hypothesized 46 y ago (13) to involve humoral signals generated in proportion to body fat stores that act in the brain to alter food intake and energy expenditure. Major candidates for such signals include the hormones insulin (14) and leptin (15), both of which are secreted in proportion to body adiposity and act in the brain to reduce food intake and promote weight loss. In contrast with short-term inputs, insulin and leptin exert effects in the CNS that are slow in onset and offset (eg, hours to days), with an effect that is sustained over long intervals. These hormones appear to regulate the activity of neuronal systems that strongly influence energy homeostasis, referred to here as central effector pathways. In this article, we advance the thesis that energy balance is achieved and maintained over long time intervals (eg, weeks to months) via the activation of key brain systems in response to a change in fat stores, triggered in part by changes in signaling by leptin and insulin (16).

	CENTRAL EFFECTOR PATHWAYS FOR CONTROL OF ENERGY BALANCE

TOP ABSTRACT INTRODUCTION CENTRAL EFFECTOR PATHWAYS FOR... CANDIDATE ANABOLIC EFFECTOR... CATABOLIC CENTRAL EFFECTOR... ROLE OF THE AUTONOMIC... SHORT-TERM, MEAL-RELATED FACTORS LONG-TERM CONTROLLERS OF... GLUCOCORTICOID SIGNALING IN THE... CONCLUSIONS REFERENCES

 
Many neuropeptides and monoamines synthesized and released along discrete neuronal pathways within the brain can modify food intake when administered to the CNS (Table 1). An increasing number of these have been implicated as endogenous signaling molecules, which play an important role in energy homeostasis. We propose that candidate central effector pathways must meet the following criteria: they strongly influence both energy intake and energy expenditure and their activity is regulated by adiposity-related signals.

	CANDIDATE ANABOLIC EFFECTOR SYSTEMS

TOP ABSTRACT INTRODUCTION CENTRAL EFFECTOR PATHWAYS FOR... CANDIDATE ANABOLIC EFFECTOR... CATABOLIC CENTRAL EFFECTOR... ROLE OF THE AUTONOMIC... SHORT-TERM, MEAL-RELATED FACTORS LONG-TERM CONTROLLERS OF... GLUCOCORTICOID SIGNALING IN THE... CONCLUSIONS REFERENCES

 
Neuropeptide Y
Neuropeptide Y (NPY) is a member of the pancreatic polypeptide family that is synthesized in peripheral sympathetic neurons as well as in the brain. In the CNS, the actions of NPY on energy homeostasis are exerted largely within the hypothalamus. The primary hypothalamic site of NPY biosynthesis is the arcuate nucleus (20), a collection of neuronal cell bodies located adjacent to the floor of the third cerebral ventricle. Axons from these neurons project to several other hypothalamic nuclei, including the paraventricular nucleus, a key brain area mediating a potent effect of NPY to stimulate feeding (21). Daily injection of NPY into the hypothalamic paraventricular nucleus not only causes sustained hyperphagia and weight gain (20–22), but also has metabolic actions that favor fat deposition. These include increased lipoprotein lipase gene expression and enzyme activity in white adipose tissue (23), enhanced lipogenesis in both liver and white adipose tissue, and increased secretion of insulin and glucocorticoids into the circulation (24). Because these metabolic effects of intracerebroventricular NPY administration are detected even when hyperphagia is prevented, they are not simply a consequence of increased energy intake. The ability of intracerebroventricular NPY to reduce SNS activity (18, 23) may account for these metabolic actions.

NPY also promotes weight gain by reducing SNS outflow to brown adipose tissue (BAT), a form of adipose tissue that is specialized for the purpose of heat production. BAT is richly supplied with SNS fibers and stimulation of these fibers elicits a thermogenic response via a process that requires a mitochondrial protein unique to BAT known as uncoupling protein 1 (UCP-1). After SNS activation of BAT, oxidation of fatty acids in mitochondria that contain UCP-1 yield energy in the form of heat rather than ATP generation. By reducing SNS outflow to BAT (18), NPY injection into the brain increases energy efficiency by suppressing this thermogenic mechanism (23).

A physiologic role for the hypothalamic NPY system in energy homeostasis is suggested by evidence that its production (within the arcuate nucleus) and release (into the paraventricular nucleus) are affected by changes in energy balance. Thus, conditions associated with weight loss, such as food deprivation (25–28) and uncontrolled insulin-deficient diabetes (29–33) increase production and release of NPY along the arcuate nucleus–paraventricular nucleus pathway, and this response may contribute to the hyperphagia common to both conditions. Activation of the hypothalamic NPY system in these conditions appears to involve decreased signaling by insulin and leptin, combined with increased glucocorticoid concentrations (26, 31, 34–36).

Genetic obesity resulting from defective leptin signaling appears to result in part from inappropriate activation of NPY-containing hypothalamic pathways. This conclusion is supported by the observation that hypothalamic NPY messenger RNA (mRNA) concentrations are elevated in fa/fa obese Zucker rats (37, 38), in ob/ob mice (39), and in db/db mice (40). Because obesity in these animals results from mutation of either the gene encoding the leptin receptor (in db/db mice and fa/fa rats) or leptin itself (in ob/ob mice), defective leptin signaling appears to activate the NPY system.

The finding that inhibition of NPY biosynthesis in the arcuate nucleus by direct application of antisense oligonucleotides is associated with reduced food intake (41) and a blunted hyperphagic response to fasting in rats (42) suggests that variations in endogenous NPY signaling contribute to the normal regulation of food intake. Similar conclusions have been drawn from studies in which hypothalamic NPY signaling was reduced by immunoneutralization (43, 44) or by intracerebroventricular infusion of antisense oligonucleotides directed to the Y₅ receptor (42), which is proposed to mediate the effects of NPY on food intake (45). However, mice with genetic NPY deficiency (due to targeted gene disruption or gene knockout) maintain relatively normal patterns of food intake and body weight gain (46); mice that lack Y₅ receptors paradoxically develop a mild, late onset form of obesity (47), as do mice lacking Y₁ receptors (48). Excessive weight gain in Y₁ receptor–deficient mice was attributed to reduced locomotor activity and occurred despite food intakes that were lower than those of controls (48). Although these findings do not support the hypothesis that NPY is required for maintenance of normal food intakes, mice lacking Y₁ receptors also have reduced food intakes in response to fasting. Y₁ receptor signaling, therefore, appears to be important for the hyperphagic response that facilitates the recovery of depleted fuel stores following food deprivation. In contrast, the effect of fasting to stimulate food intake is intact in mice lacking NPY (46). These conflicting results raise the possibility that genetic deficiency of a major CNS signaling system can result in a compensatory "rewiring" of neuronal circuits involved in energy homeostasis, and that the extent to which this occurs can vary with the nature of the mutation. Alternatively, CNS pathways that control food intake may be sufficiently redundant to compensate for the loss of even a major signaling system. This possibility agrees with a growing literature suggesting that neuronal systems additional to NPY play an important role in weight regulation.

Melanin concentrating hormone and orexins
Melanin concentrating hormone (MCH) (49) and orexins A and B (50), also referred to as hypocretins 1 and 2 (51), are hypothalamic neuropeptides that share several features in common and are implicated in the stimulatory control of food intake. Both peptides are expressed exclusively in the dorsolateral hypothalamus and both have extensive projections to other brain areas (49, 50). Both peptides also stimulate food intake robustly after injection into brain ventricles, and expression of mRNA encoding these peptides increases in response to fasting, features in common with NPY. These results suggest that the hyperphagic response to conditions associated with weight loss involves the activation of multiple neuropeptide systems in the hypothalamus. The mechanisms underlying the regulation of these MCH and orexin neurons, however, are unknown, and the possibility that both neuropeptides are expressed within the same neurons has yet to be explored. Although the hypothesis that these neurons are targets for the action of negative feedback from hormones such as leptin and insulin is attractive, the receptors for these hormones are not abundantly expressed in the dorsolateral hypothalamus compared with areas such as the arcuate nucleus (34, 52). Regulation of these neuronal systems by leptin or insulin, if it occurs, is likely to involve an indirect signaling pathway.

	CATABOLIC CENTRAL EFFECTOR PATHWAYS

TOP ABSTRACT INTRODUCTION CENTRAL EFFECTOR PATHWAYS FOR... CANDIDATE ANABOLIC EFFECTOR... CATABOLIC CENTRAL EFFECTOR... ROLE OF THE AUTONOMIC... SHORT-TERM, MEAL-RELATED FACTORS LONG-TERM CONTROLLERS OF... GLUCOCORTICOID SIGNALING IN THE... CONCLUSIONS REFERENCES

 
Melanocortins
The melanocortin signaling system in the brain is an important member of the family of catabolic central effector pathways proposed to transduce changes in CNS leptin signaling into changes in food intake and body weight. Melanocortins are a family of peptides, including -melanocyte-stimulating hormone (-MSH) and corticotropin, that are cleaved from the proopiomelanocortin precursor. In the mammalian forebrain, proopiomelanocortin is expressed solely by neurons of the arcuate nucleus, adjacent to NPY-producing cells. These neurons release -MSH from axon terminals (53), where it can bind to and activate melanocortin receptors on postsynaptic membrane surfaces. Of the 5 melanocortin receptor subtypes identified to date, 2 are expressed primarily in the brain (MC3 and MC4 receptors) (54). The MC4 receptor is strongly implicated in energy homeostasis because genetic knockout of this receptor subtype causes hyperphagia and obesity in mice (55) (Table 2) and because intracerebroventricular administration of an MC4 receptor agonist causes anorexia, whereas antagonists of MC4 receptors stimulate feeding (56). These observations implicate the melanocortin system as a catabolic effector pathway that plays a key role in energy homeostasis.

Agouti and agouti-related protein: endogenous melanocortin receptor antagonists
A unique feature of the melanocortin system is the presence of endogenous antagonists of melanocortin receptors. The first of these to be discovered is agouti, a protein synthesized in skin and hair follicles that is released in a paracrine manner to antagonize -MSH at cutaneous MC1 receptors (60). This mechanism explains the lightening effect of agouti on coat color because melanin production in hair follicles is stimulated by the ability of circulating -MSH to bind to and activate cutaneous MC1 receptors. Evidence that antagonism of CNS melanocortin receptors can cause obesity was first provided in the yellow obese or agouti (A^y) mouse, an autosomal dominant model of genetic obesity (Table 2). This condition results from a gene rearrangement that causes ubiquitous expression of agouti in tissues throughout the body, including the brain. Because agouti antagonizes MC4 receptors as well as MC1 receptors, this form of obesity appears to result from antagonism of melanocortin receptors in the brain, whereas the yellow coat color arises from antagonism of the melanocortin receptors in the hair follicle (60).

A second endogenous melanocortin receptor antagonist, known as agouti-related protein (AgRP), was identified recently based on sequence homology to the agouti gene (61). In contrast with agouti, the gene encoding AgRP is normally expressed in the CNS (61) and appears to function as an endogenous antagonist of CNS melanocortin receptors (62). Consistent with this hypothesis, AgRP antagonizes -MSH at both MC3 and MC4 receptors, but not at MC1 receptors (62). Moreover, transgenic overexpression of AgRP in tissues throughout the body (by using a ß-actin promoter) causes an obesity syndrome in mice that is virtually identical to that associated with overexpression of agouti, except that coat color is not affected in AgRP-transgenic mice (62), presumably because AgRP does not antagonize cutaneous MC1 receptors. In the brain of normal animals, mRNA encoding AgRP is expressed only in the arcuate nucleus (61) and AgRP mRNA is highly co-localized with NPY, but not with proopiomelanocortin mRNA in arcuate nucleus neurons (63). Like NPY, expression of AgRP mRNA is also strongly induced by fasting and leptin deficiency, suggesting that AgRP and NPY gene expression are regulated in parallel within the same arcuate nucleus neurons (63). The arcuate nucleus, therefore, appears to contain a unique neuronal subtype (NPY/AgRP neuron) that, when activated, exerts dual effects to promote hyperphagia and weight gain by activating NPY receptors on the one hand and by antagonizing melanocortin receptors on the other.

Corticotropin-releasing hormone
In addition to its well-known role as a major controller of hypothalamic-pituitary-adrenal axis activity, corticotropin-releasing hormone (CRH) is well-suited to function as a catabolic central effector molecule. Administration of this 41–amino acid peptide into the paraventricular nucleus, the primary site of CRH biosynthesis and an area with abundant CRH receptors, elicits a constellation of effects that promotes a state of negative energy balance and weight loss. These include suppression of food intake (64) coupled with stimulation of SNS outflow (64, 65), which increases lipolysis (65) and activates BAT thermogenesis (66). Moreover, chronic central CRH administration reduces food intake and body weight in normal rats (64), genetically obese rats (67), rats rendered obese by lesions to the ventromedial hypothalamic nucleus (VMN) (68), and primates (69). That endogenous CRH participates in energy homeostasis is suggested by the increase of CRH mRNA concentrations in the paraventricular nucleus documented in several conditions associated with anorexia and weight loss. These include adrenalectomy (17), involuntary overfeeding (70), and administration of leptin (34) or cytokines such as interleukin 1ß (71, 72). Conversely, conditions associated with hyperphagia and activation of anabolic effector pathways, including food deprivation (73) and insulin-deficient diabetes (31), are associated with reduced CRH expression in rat hypothalamus. Changes in hypothalamic CRH signaling may therefore contribute to adaptive changes in energy balance in these conditions.

An important effect of glucocorticoids in the brain is to inhibit hypothalamic CRH expression, which may contribute to the effect of glucocorticoid excess to promote hyperphagia and weight gain (17, 74). Regulation of hypothalamic production and release of CRH may, therefore, be an important site at which glucocorticoids and leptin interact in the control of energy balance. This interaction provides a plausible explanation for the effect of adrenalectomy to increase responsiveness to leptin in a rat model (75).

Cocaine- and amphetamine-regulated transcript
Cocaine- and amphetamine-regulated transcript (CART) is widely expressed in the brain, including hypothalamic areas such as the arcuate nucleus, paraventricular nucleus, and dorsomedial hypothalamic nucleus (76, 77), and encodes a neuropeptide with potent, but short-lived anorexic effects after intracerebroventricular administration (76, 78). The finding that food intake increases after intracerebroventricular infusion of antisera raised against the CART peptide suggests that it functions as an endogenous inhibitor of feeding (78, 76). Moreover, hypothalamic expression of CART is reduced by fasting and by both genetic leptin deficiency (in ob/ob mice) and leptin resistance (in fa/fa rats) (76). Support for the hypothesis that hypothalamic CART expression is regulated by leptin was provided by a study in which leptin treatment of ob/ob mice was shown to markedly increase CART mRNA in the arcuate nucleus (76). These data suggest strongly that CART peptide is a member of the family of catabolic central effector pathways that participates in the CNS response to leptin.

	ROLE OF THE AUTONOMIC NERVOUS SYSTEM IN THE CONTROL OF ENERGY BALANCE

TOP ABSTRACT INTRODUCTION CENTRAL EFFECTOR PATHWAYS FOR... CANDIDATE ANABOLIC EFFECTOR... CATABOLIC CENTRAL EFFECTOR... ROLE OF THE AUTONOMIC... SHORT-TERM, MEAL-RELATED FACTORS LONG-TERM CONTROLLERS OF... GLUCOCORTICOID SIGNALING IN THE... CONCLUSIONS REFERENCES

 
Autonomic outflow is regulated by many of the same brain regions involved in the control of food intake. These include the lateral hypothalamic area (LHA), VMN, and paraventricular nucleus. Moreover, the effects of brain peptides and monoamines on energy expenditure and metabolism in peripheral tissues are likely to be mediated via changes in autonomic outflow (17, 18). Therefore, the autonomic nervous system seems likely to be the key efferent mechanism by which central effector pathways influence energy expenditure and metabolism. For example, activation of the SNS, which promotes energy dissipation and weight loss, can be stimulated by CRH and inhibited by NPY. Regulation of SNS outflow, therefore, may help to mediate the effect of these peptides on energy homeostasis.

Activity of the SNS increases in response to feeding (17, 79) and contributes to the thermic effect of food, 5–10% of daily energy expenditure (80), and involves activation of BAT in rodents. When energy intake increases, as during the consumption of a highly palatable "cafeteria" diet, thermogenesis increases proportionately via an SNS-dependent mechanism (81, 82) and thereby limits weight gain. Conversely, fasting and energy restriction reduce SNS activation of BAT and decrease energy expenditure (79). Therefore, increased SNS activity during states of positive energy balance contributes to the compensatory elevation of energy expenditure that limits excess fat storage, whereas reduced SNS tone is a component of the adaptive response to starvation. Although the mechanisms underlying regulation of SNS outflow are incompletely understood, they may involve changes in central effector pathway activity in response to changing input from adiposity-related hormones.

Although an important role for BAT thermogenesis in energy homeostasis is widely accepted, adult humans do not have discrete BAT depots. Therefore, questions exist about the role of thermogenic uncoupling in human energy homeostasis. The recent discovery that human skeletal muscle and other tissues express 2 related mitochondrial uncoupling proteins, UCP-2 and UCP-3, has generated interest in the hypothesis that control of energy expenditure in humans and other mammals involves hormonal regulation of thermogenic uncoupling at diffuse sites throughout the body (83, 84).

Many experimental models of obesity are accompanied by an impaired SNS response to food intake and other stimuli. These forms of experimental obesity are therefore proposed to result, at least in part, from an impaired SNS response to the ingestion of nutrients (17). According to this hypothesis, impairment of sympathetically mediated thermogenesis results in a diversion of ingested energy into fat stores and is therefore a major factor in the pathogenesis of obesity. This mechanism was forwarded to explain obesity in mice with transgenic ablation of BAT (85).

An alternative hypothesis, however, is that defective SNS function contributes to obesity only when it is the consequence of disordered regulation of central effector system activity. According to this proposal, a defect in thermogenesis resulting from impaired SNS activation does not, in and of itself, cause obesity. This is because the ability of increased energy efficiency to promote weight gain is limited by increased negative feedback signaling to central effector pathways that accompanies weight gain. Thus, although reduced energy expenditure may favor a positive state of energy balance and promote weight gain, this effect should be limited by increased CNS signaling mediated by adiposity signals such as leptin and insulin. The predicted outcome of an isolated reduction of energy expenditure is the development of a new steady state of energy balance after an initial expansion of adipose mass. The degree to which weight gain occurs, according to this model, depends on the degree to which energy efficiency is increased on the one hand, and on the robustness with which the CNS responds to increased negative feedback signaling on the other hand. This hypothesis is supported by the observation that mice with impaired SNS activity due to genetic deficiency of either norepinephrine (86) or UCP-1 (87) do not develop obesity, despite unambiguous defects in thermogenesis.

How then does transgenic ablation of BAT cause obesity in mice (85)? One possibility is that obesity in these animals involves defects additional to reduced thermogenesis. Indeed, these BAT-deficient mice exhibit hyperphagia (88), suggesting that impaired negative feedback control of adiposity also exists in these mice. Consistent with this possibility, BAT-deficient mice are markedly resistant to anorexia induced by leptin (89). We therefore favor the hypothesis that reduced energy expenditure may lead to weight gain, but is unlikely to cause obesity in the absence of a defect in the CNS control of energy homeostasis.

	SHORT-TERM, MEAL-RELATED FACTORS

TOP ABSTRACT INTRODUCTION CENTRAL EFFECTOR PATHWAYS FOR... CANDIDATE ANABOLIC EFFECTOR... CATABOLIC CENTRAL EFFECTOR... ROLE OF THE AUTONOMIC... SHORT-TERM, MEAL-RELATED FACTORS LONG-TERM CONTROLLERS OF... GLUCOCORTICOID SIGNALING IN THE... CONCLUSIONS REFERENCES

 
Our model groups the many stimuli that are capable of inducing an acute change in energy balance, in a manner that is unrelated to the level of adiposity, into the category of short-term meal-related or situational factors. This grouping encompasses a wide variety of both endogenous and exogenous stimuli that range from physiologic signals generated in response to a meal to behavioral and autonomic responses to social situations or to an environmental stress (eg, the fight or flight response). It should be emphasized that although the long-term regulation of energy homeostasis serves to minimize the effect of these diverse inputs on body fat stores, the level of adiposity may be affected if a change in the input from these short-term signals is sustained over long time intervals. This is particularly true for emotional factors and for changes in diet composition, both of which may influence body weight. The extent to which such inputs influence the regulated amount of body fat may therefore depend on the degree to which compensatory changes in long-term adiposity signaling occur in response to a change in body fat. The role of short-term, meal-related signals in energy homeostasis is illustrated here by the examples of glucose utilization and gastrointestinal peptide hormones.

Glucose utilization
The concept that consumption of a meal produces changes in fuel utilization that influence single-meal food intake is supported by evidence spanning 4 decades of investigation [reviewed in (90)]. The glucostatic theory for the control of feeding, reviewed by Mayer and Thomas (91), states that the body monitors its energy needs via glucoreceptive brain neurons that are responsive to their own rate of glucose utilization. Accordingly, a fall in the level of glucose utilization by these glucose-sensitive neurons was proposed to stimulate food intake, whereas the effect of a meal to increase glucose utilization led to satiety by activating glucose-responsive neurons. These effects of glucose were proposed to take place in a "hunger center" located in the LHA, which when it has bilateral lesions causes anorexia and weight loss in rats, and in a "satiety center" located within the VMN, which, when it has bilateral lesions produces obesity. These concepts were combined into a broadly accepted proposal (92) that glucoreceptive neurons governed the activity of these dual centers in the control of feeding behavior.

This dual-center model is challenged, however, by the finding that animals with VMN lesions remain responsive to glucopenia as a stimulus for feeding (93, 94) and that after a dynamic phase of weight gain, these animals regain relatively normal patterns of food intake (95, 96). Rather than manifesting a complete failure of body weight regulation due to the absence of satiety, animals with VMN lesions simply regulate fuel stores at higher than normal rates. These observations suggest that bilateral VMN lesions interrupt one or more catabolic central effector pathways, thereby favoring a positive state of energy balance, whereas pathologic weight loss associated with bilateral LHA lesions may result from the loss of key anabolic signaling pathways. That MCH- and orexin-containing neurons are localized primarily in the dorsal aspect of the LHA raises the possibility that damage to these neuropeptide systems may contribute to the effect of LHA lesions on energy homeostasis.

Although hypoglycemia stimulates food intake, the role of glucose utilization in normal feeding is clouded by evidence that pathologic cellular glucopenia is necessary to elicit a feeding response (97, 98). Glucose-sensitive neurons, therefore, may simply be components of an emergency reflex loop that defends against acute hypoglycemia (97). However, recent studies using continuous measurements of blood glucose concentrations in rats have documented a small, transient decline in plasma glucose concentrations just before the onset of spontaneous meals. This pattern of change in circulating glucose concentrations predicts impending meals sufficiently to be potentially causal, and experimental induction of the decline in glucose is reported to initiate eating (99). The possibility that the premeal decline in glucose is a component of the anticipatory response to nutrient ingestion, rather than a signal that induces the meal, however, has yet to be excluded (100). The hypothesis that changes in blood glucose concentrations participate in normal meal initiation, therefore, requires further study.

Available data do not support the concept that the rate of CNS glucose utilization plays a major role in long-term body weight regulation. First, neither the fasting plasma glucose concentration nor the rate of whole-body glucose utilization vary with differences in body adiposity in normal humans (101, 102). These indexes are therefore unlikely to convey afferent information related to fuel stores. Moreover, whereas chronic intravenous glucose infusion suppresses food intake in normal animals, hyperglycemia occurring in insulin-deficient diabetes mellitus is associated with hyperphagia. An alternative explanation that accounts for these disparate observations is that the relation between changes in blood glucose concentrations and CNS control of energy homeostasis arise from associated changes in circulating concentrations of insulin, leptin, and glucocorticoids, rather than via altered glucose utilization per se.

Gastrointestinal peptides as satiety factors
Nutrient ingestion stimulates secretion into the bloodstream of numerous gastroenteropancreatic hormones, which helps to coordinate the digestive functions that process a meal. The central role of gastroenteropancreatic hormones in digestion led to the hypothesis that a subset of these hormones also participates in the control of satiety. To date, many peptide hormones secreted by the gut have been shown to decrease meal size, and an important physiologic role has been suggested for the peptide cholecystokinin in the control of meal size.

In 1973, Gibbs et al (103) reported that intraperitoneal injection of cholecystokinin reduces meal size in rats. The observation that administration of cholecystokinin intraperitoneally is more effective than intravenous administration (104) suggests that targets within the abdominal cavity are important for cholecystokinin-induced satiety. Subsequently, it was found that the vagus nerve, which conveys parasympathetic activity to and fro between the brain and the gut, is a target for cholecystokinin's effects on feeding. The mechanism by which cholecystokinin promotes satiety is hypothesized to involve both inhibition of gastric emptying (105, 106), which stimulates vagal afferents sensitive to gastric distention, and direct activation of vagal afferent fibers that terminate in the brainstem. Evidence to support the latter mechanism includes the finding that cholecystokinin receptors are present on afferent vagus nerve fibers and that the satiety effect of peripherally administered cholecystokinin requires an intact abdominal vagus nerve (107, 108). Gastric vagal afferents that are responsive to cholecystokinin (109) terminate on cell bodies in the nucleus tractus solitarius (110), the primary brain area for processing afferent information from the gastrointestinal tract.

Several aspects of cholecystokinin action exemplify the distinction between short-term, meal-related factors and long-term hormonal signals that regulate adiposity. This difference is illustrated in a study in which intraperitoneal administration of cholecystokinin to free-feeding rats before each meal resulted in a consistent reduction in meal size of 50% (111). Rather than continuing to lose weight, however, the rats responded to this challenge by eating these smaller meals about twice as often. Despite a pronounced change in single meal size; therefore, overall food intake and body weight were essentially unaffected. The satiety effect of intraperitoneal cholecystokinin is also dependent on an intact vagus nerve (108), whereas the maintenance of normal body adiposity is not (90). Short-term signals such as cholecystokinin, therefore, do not appear to convey input to the CNS that is critical to the maintenance and defense of the level of adipose mass. Rather, their effects on energy balance can be overridden by control mechanisms that operate over long time intervals to regulate fuel stores.

Implicit in our model of energy homeostasis is a mechanism for integrating input from short-term, meal-related signals into the long-term control of energy balance. One hypothesis to explain this integration is that the response of the brain to short-term signals is influenced by the prevailing concentration of circulating adiposity signals. This hypothesis is supported by the observation that satiety induced by intraperitoneal cholecystokinin administration is potentiated by intracerebroventricular infusion of insulin (112) or systemic injection of leptin (113). Long-term controllers of energy balance, therefore, may regulate adipose stores in part by modulating the sensitivity of short-term signals such as cholecystokinin.

	LONG-TERM CONTROLLERS OF ADIPOSITY

TOP ABSTRACT INTRODUCTION CENTRAL EFFECTOR PATHWAYS FOR... CANDIDATE ANABOLIC EFFECTOR... CATABOLIC CENTRAL EFFECTOR... ROLE OF THE AUTONOMIC... SHORT-TERM, MEAL-RELATED FACTORS LONG-TERM CONTROLLERS OF... GLUCOCORTICOID SIGNALING IN THE... CONCLUSIONS REFERENCES

 
In contrast with the diverse nature of short-term signals that regulate single meal size, long-term signals involved in the control of adiposity appear to be few in number and to play a highly specialized role. These hormonal signals not only influence signaling by central effector pathways to favor a particular shift in energy balance, but they also modulate the sensitivity of the brain to afferent inputs generated in response to short-term factors. During weight loss, therefore, a reduced concentration of long-term adiposity signals is proposed to 1) diminish the efficacy of satiety-inducing inputs, 2) suppress catabolic effector pathways, and 3) activate anabolic effector pathways. This highly integrated set of responses to weight loss is proposed to stimulate feeding and to reduce energy expenditure, thereby ensuring the recovery of depleted fuel stores (114).

Leptin
The hypothesis that adipocytes secrete an adiposity-related negative feedback signal was first advanced by Kennedy (13) 46 y ago and the recent discovery of leptin has confirmed this hypothesis. Evidence supporting a major role for leptin in energy homeostasis has accumulated rapidly after an initial study (15) in which the ob gene was cloned and sequenced. The ob gene product leptin is a 164-kDa protein that is transcribed in adipocytes of a variety of species, including humans, and after cleavage of a signal peptide is secreted into the bloodstream where it circulates at concentrations proportional to body fat mass in rodents (115, 116) and humans (115, 117–121). Consistent with the hypothesis that changes in fat mass are transmitted to the CNS by changes in leptin concentrations, plasma leptin concentrations decrease after weight loss (115, 118) and are strongly correlated with leptin concentrations in cerebrospinal fluid (122).

A fundamental observation implicating leptin in body weight regulation is that leptin deficiency due to a loss-of-function mutation of the ob gene results in hyperphagia and massive obesity in ob/ob mice (Table 2). The CNS responds to the absence of leptin as it would to a poverty of fat stores: by increasing food intake, decreasing energy expenditure, and activating metabolic responses that promote the deposition of fat. Accordingly, leptin replacement in ob/ob mice should normalize body weight and composition and supranormal leptin concentrations achieved by exogenous administration should reduce fat stores. These predictions have been confirmed in studies of intravenous (123), subcutaneous (124), intraperitoneal, (125–130), and intracerebroventricular leptin administration (124, 125, 131). Complementing its anorexic effects, leptin also increases energy expenditure and normalizes the reduced metabolic rate and body temperature characteristic of ob/ob mice (127). This effect may result from SNS activation, because intravenous leptin infusion increases the firing rate of SNS nerves, which innervate muscle, BAT, kidney, and adrenal gland in anesthetized rats (132).

As occurs in mice, genetic leptin deficiency in humans is associated with profound hyperphagia and weight gain (133), and mutation of the leptin receptor is also accompanied by severe obesity in humans (134). Although impaired leptin signaling is probably a rare cause of human obesity, these data support the hypothesis that leptin plays a critical role in human body weight regulation. Abnormal neuroendocrine function accompanies mutation of the leptin receptor in humans, suggesting an important role for leptin in endocrine regulation as well as in energy homeostasis. Consistent with this hypothesis, female ob/ob and db/db mice are infertile because of hypothalamic hypogonadism. When treated with leptin, normal reproductive function is restored to female ob/ob mice (135, 136), an effect that cannot be reproduced by weight loss alone. Similarly, leptin treatment of male ob/ob mice elevates follicle-stimulating hormone concentrations and increases testicular and seminal vesicle mass, which improves fertility (136). The finding that the effect of fasting in normal mice—suppression of the gonadotrophic, thyroid, and hypothalamic-pituitary-adrenal axes—is attenuated by leptin administration (137) suggests that leptin deficiency is a key mediator of these responses. Flier (138) has argued cogently that a falling leptin concentration is an important signal to the brain that body fuel stores are threatened and is therefore a key aspect of leptin's evolutionary function in humans.

Leptin also appears to be important for normal glucose homeostasis because leptin administration ameliorates the obesity-associated hyperinsulinemia and hyperglycemia of ob/ob mice (127). Leptin administration inhibits hepatic glycogenolysis in normal rats, an effect that is accompanied by increased fat oxidation in the liver (139). Leptin is also reported to inhibit insulin secretion via a direct effect on ß cells (140). Although these studies are provocative, the importance of leptin in glucose homeostasis in normal animals remains uncertain.

Leptin targets
The finding that food intake and body weight are reduced by low doses of leptin administered into the cerebroventricular system of mice (124, 125, 141) and rats (131) suggests that its metabolic and feeding effects are mediated in the brain. Consistent with this hypothesis, leptin is present in human cerebrospinal fluid in concentrations that are strongly correlated with plasma leptin concentrations (122), and leptin receptors (also termed OB-R) are present in various brain regions including the hypothalamus (34, 142, 143). There are 6 splice variants of the leptin receptor (142), only 1 of which (OB-Rb) is abundantly and preferentially expressed in the hypothalamus. This long form of the leptin receptor is strongly implicated in leptin signal transduction because it contains an intracellular domain with homology to receptors of the cytokine family that appears to mediate intracellular leptin signaling via the Janus kinase—signal transducers and activators (JAK-STAT) of the transcription pathway to control gene transcription (144). The observation that OB-Rb is abnormally spliced in mice homozygous for the db mutation (db/db mice) (142), which are phenotypically identical to ob/ob mice on the same strain background (145), established an important role for the long form of the leptin receptor in body weight regulation (Table 2).

The finding that both ob/ob and db/db mice have an elevated expression of OB/Rb in the arcuate nucleus (146) suggests that leptin itself may participate in the control of hypothalamic leptin receptor gene expression. Similarly, fasting in normal rats is associated with a sharp decrease in leptin concentrations and with increased OB-Rb mRNA concentrations in the arcuate nucleus. Because ob/ob mice have increased sensitivity to the anorexic effects of leptin, changes in hypothalamic leptin receptor expression are one factor that may help to explain genetic or acquired differences in leptin responsiveness.

Both ob/ob and db/db mice overexpress the NPY gene in the arcuate nucleus (39, 40). Because prolonged administration of NPY into rodents elicits behavioral, autonomic, and metabolic responses characteristic of ob/ob and db/db mice [eg, hyperphagia, reduced energy expenditure, obesity, hyperglycemia, hyperinsulinemia, hypercortisolemia, and hypogonadism (23, 24, 147)], overproduction of hypothalamic NPY in these mice may contribute to their obesity syndrome. If leptin deficiency is the cause of overexpression of hypothalamic NPY in ob/ob mice, then leptin administration should attenuate NPY gene expression in ob/ob mice, but not in db/db mice. These predictions have been confirmed (124, 148). Evidence that NPY plays a crucial role in the pathogenesis of obesity in ob/ob mice was provided in a study in which NPY knockout mice were crossed into the ob/ob genotype (130) to create leptin-deficient mice that lack NPY; these mice have an attenuated obesity syndrome (by 50%). Thus, NPY is required for the complete response to leptin deficiency. This dependence of obesity in leptin-deficient mice on NPY signaling does not appear to involve the Y₅ receptor because obesity is not attenuated in ob/ob mice lacking this receptor subtype (47).

It is becoming increasingly clear, however, that NPY is but one of many hypothalamic systems that responds to leptin in the regulation of energy balance. Pathways that stimulate food intake and promote weight gain (eg, NPY, MCH, AgRP, and orexins) appear to be inhibited by leptin, activated during fasting, or both, whereas those pathways that promote anorexia and weight loss (eg, melanocortins, CART, thyrotropin-releasing hormone, and CRH) are stimulated by leptin. Thus, a highly integrated and redundant system of neuronal pathways appears to mediate the CNS response to a change in leptin signaling.

Regulation of ob gene expression and leptin secretion
In rodents, weight loss reduces both adipocyte ob gene expression and circulating leptin concentrations (115, 116, 149–152) and refeeding rapidly normalizes ob mRNA concentrations (149). Ob gene expression is elevated in most rodent models of obesity, including fa/fa obese Zucker rats (153), rats and mice with VMN lesions (116, 154), yellow obese (A^y) mice (150), mice with transgenic BAT deficiency (116), mice with knockout of the MC4 receptor (55), and mice with diet-induced obesity (125, 150, 155). Thus, excessive deposition of body fat elicits the expected increase in circulating leptin, an observation that raises the possibility that resistance to leptin may accompany most forms of rodent obesity.

Concentrations of plasma leptin and adipocyte ob mRNA in humans also decrease with weight loss (115, 118) and increase with weight gain (115). Interestingly, one study (118) found that a diet-induced reduction of 10% of body weight was associated with a 53% reduction in serum leptin concentrations when measured during the end of the weight-loss period, but that leptin concentrations tended to increase during the weight-maintenance period, despite no change in weight. This observation suggests that, in addition to the level of fat stores, leptin secretion is sensitive to changes in energy balance (156).

In humans, leptin concentrations do not change acutely with meal consumption and do not fluctuate with acute changes in endogenous insulin or glucose concentrations (117). Leptin, therefore, is not a satiety signal. Rather, circulating leptin concentrations exhibit a circadian rhythm in human subjects, being highest around midnight and lowest around noon (117). In contrast, mRNA concentrations in ob rats increase sharply during the dark phase when rats are actively eating and are lowest during the light phase (149); a similar pattern was reported for plasma leptin concentrations in mice (137). The mechanisms underlying the circadian leptin rhythm and the differences in this rhythm between rodents and humans remain unknown.

Insulin may participate in the control of leptin secretion. In rodents, ob gene expression increases after insulin administration, both without (149, 150) and with (150, 152) concomitant infusions of glucose. Insulin also exerts direct effects on adipocyte leptin synthesis and secretion (157, 158). In humans, however, short-term (up to 5 h) hyperinsulinemic, euglycemic, and hyperglycemic clamps do not stimulate increases in circulating leptin (120, 121), although leptin concentrations do increase during more prolonged insulin infusion (120). Glucocorticoids may also increase ob gene expression and leptin secretion from adipocytes (158, 159). However, a physiologic role for glucocorticoids in the control of leptin production has yet to be shown. Indeed, fasting (149, 150) and uncontrolled diabetes (160) reliably lower ob gene expression and leptin secretion despite increased circulating glucocorticoid concentrations (35). If glucocorticoids do stimulate leptin secretion, therefore, this effect can be overridden by other factors during conditions such as fasting.

Role of insulin signaling in the CNS
Like leptin concentrations, plasma insulin concentrations vary in proportion to body adiposity (10, 101, 102, 161). The hypothesis that insulin secreted from the pancreas enters the CNS, where it acts as a humoral feedback regulator of food intake and energy balance (14), was first supported by the observation that chronic intracerebroventricular insulin administration in baboons caused a dose-dependent reduction in food intake and body weight (162). This finding was subsequently confirmed in rats (31, 163, 164), sheep (165), and marmots (166). Insulin receptors (52) and related intracellular signaling molecules such as insulin receptor substrate 1, which are concentrated in hypothalamic areas such as the arcuate nucleus (167), may mediate insulin's effects on food intake. Circulating insulin enters the CNS after intravenous infusion (162, 168–172) via a saturable transport mechanism (173). The kinetics of this process are consistent with transport mediated via insulin receptors (173) expressed on the luminal surface of brain microvessels (174). The efficiency of transport via the BBB insulin receptor is sufficiently high that it has been used as a mechanism for delivery of protein pharmaceuticals that do not otherwise enter the brain. According to this strategy, the protein of interest is conjugated to an insulin receptor antibody, which greatly increases its transport across the BBB receptor in a primate model (175).

During systemic infusion, insulin's effects in the CNS to promote a state of negative energy balance are opposed by potent anabolic effects exerted in peripheral tissues. This is particularly evident in the treatment of uncontrolled insulin-dependent diabetes, whereby the normalization of blood glucose concentrations with insulin treatment causes weight gain despite reduced food intake (176). The potential for systemic insulin administration to cause weight gain contrasts sharply with the weight loss associated with central insulin infusion, even in rats with uncontrolled diabetes (31).

One mechanism by which insulin may participate in energy homeostasis is via its effect to inhibit hypothalamic expression of NPY (26, 31). Central insulin infusion also potentiates the satiety effect of peripherally administered cholecystokinin (112, 177). Elevated brain insulin concentrations may therefore promote a state of negative energy balance both by inhibiting anabolic effector pathways (eg, NPY) and by increasing sensitivity to peripheral satiety signals such as cholecystokinin.

	GLUCOCORTICOID SIGNALING IN THE CNS

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In peripheral tissues, glucocorticoids exert catabolic actions that promote the loss of lean body mass. In contrast, the effects of glucocorticoids on the CNS tend to be anabolic in the sense that they increase food intake and promote a state of positive energy balance. Consistent with this view, glucocorticoid deficiency induced by adrenalectomy causes anorexia and weight loss (an effect that is pronounced in most rodent forms of obesity) and these effects are reversed by glucocorticoid replacement. However, glucocorticoid excess per se does not cause a dose-dependent increase in food intake or body weight in normal animals. One potential explanation for this observation is that glucocorticoids have actions in the CNS that oppose those of insulin and leptin. Because glucocorticoid administration increases circulating insulin and leptin concentrations, any CNS action of systemically administered glucocorticoids to increase energy balance may be opposed by increased negative feedback signaling to the brain (35, 36, 178).

Because circulating glucocorticoid concentrations are sensitive to factors other than adiposity and energy balance (eg, stress), we do not view glucocorticoids as adiposity-related negative feedback signals. Rather, glucocorticoids appear to antagonize the CNS response to insulin and leptin and thereby promote a state of positive energy balance. Thus, the anorexic response to intracerebroventricular leptin (75) or insulin (179) is potentiated by adrenalectomy in rats, and this effect is reversed by glucocorticoid replacement. Furthermore, leptin and insulin inhibit hypothalamic NPY and leptin stimulates hypothalamic CRH gene expression (34), whereas glucocorticoids exert the opposite effects (17, 35, 180). These observations suggest that interactions of leptin, insulin, and glucocorticoids at the level of central effector pathways may play an important role in energy homeostasis.

	CONCLUSIONS

TOP ABSTRACT INTRODUCTION CENTRAL EFFECTOR PATHWAYS FOR... CANDIDATE ANABOLIC EFFECTOR... CATABOLIC CENTRAL EFFECTOR... ROLE OF THE AUTONOMIC... SHORT-TERM, MEAL-RELATED FACTORS LONG-TERM CONTROLLERS OF... GLUCOCORTICOID SIGNALING IN THE... CONCLUSIONS REFERENCES

 
In summary, our model of energy homeostasis proposes that long-term adiposity-related signals such as insulin and leptin influence the neuronal activity of central effector pathways that serve as controllers of energy balance. Because these hormones circulate at concentrations that are proportionate to fat mass and energy balance, a change in body fat stores sufficient to alter the delivery of these hormones to the brain induces central effector pathway responses that promote the return of adiposity to its original value. Superimposed on this long-acting control system are short-term situational and meal-related signals that arise from many sources, including the gastrointestinal tract, the environment, and higher centers in the brain. Although these inputs can exert potent effects on meal initiation, meal size, and meal frequency, their effect on body fat content is limited by compensatory changes in the level of adiposity signals. Through this mechanism, body fuel stored in the form of adipose tissue tends to remain constant despite short-term mismatches in energy balance.

	FOOTNOTES

 
¹ From the Departments of Medicine, Biological Structure, and Psychology, University of Washington, Harborview Medical Center and the VA Puget Sound Health Care System, Seattle; and the Department of Psychiatry, University of Cincinnati.

² Supported by grants from the NIH (DK-12829, DK-52989, and NS-32273), the Diabetes Endocrinology Research Center and Clinical Nutrition Research Unit at the University of Washington, and the VA Merit Review Program.

³ Address reprint requests to MW Schwartz, Department of Medicine, University of Washington and the VA Puget Sound Health Care System, 1660 South Columbian Way, Seattle, WA 98108. E-mail: mschwart{at}u.washington.edu.

	REFERENCES

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