s u p p l e m e n t

Central Control of Body Weight and Appetite

Stephen C. Woods and David A. D’Alessio

Departments of Psychiatry (S.C.W.) and Medicine (D.A.D.), University of Cincinnati, Cincinnati, Ohio 45237

Context: Energy balance is critical for survival and health, and control of food intake is an integralpart of this process. This report reviews hormonal signals that influence food intake and theirclinical applications.

Evidence Acquisition: A relatively novel insight is that satiation signals that control meal size andadiposity signals that signify the amount of body fat are distinct and interact in the hypothalamusand elsewhere to control energy homeostasis. This review focuses upon recent literature address-ing the integration of satiation and adiposity signals and therapeutic implications for treatmentof obesity.

Evidence Synthesis: During meals, signals such as cholecystokinin arise primarily from the GI tractto cause satiation and meal termination; signals secreted in proportion to body fat such as insulinand leptin interact with satiation signals and provide effective regulation by dictating meal size toamounts that are appropriate for body fatness, or stored energy. Although satiation and adipositysignals are myriad and redundant and reduce food intake, there are few known orexigenic signals;thus, initiation of meals is not subject to the degree of homeostatic regulation that cessation of eatingis. There are now drugs available that act through receptors for satiation factors and which causeweight loss, demonstrating that this system is amenable to manipulation for therapeutic goals.

Conclusions: Although progress on effective medical therapies for obesity has been relatively slowin coming, advances in understanding the central regulation of food intake may ultimately beturned into useful treatment options. (J Clin Endocrinol Metab 93: S37–S50, 2008)

The past decade has seen an increasing recognition that a com-plex interplay exists between the central nervous system

(CNS) and the activity of numerous organs involved in energyhomeostasis. This requires the transmission of key informationto the brain, and control of food intake is one component ofenergy balance where endocrine signaling from the periphery tothe CNS has a particularly important role. Considered broadly,energy homeostasis consists of the interrelated processes inte-grated by the brain to maintain energy stores at appropriatelevels for given environmental conditions. Energy homeostasisthus includes the regulation of nutrient levels in key storage or-gans (e.g. fat in adipose tissue and glycogen in the liver andelsewhere) as well as in the blood (e.g. blood glucose). To ac-complish this, the brain receives continuous information aboutenergy stores and fluxes in critical organs, about food that is

being eaten and absorbed, and about basal and situational en-ergy needs by tissues. The brain in turn controls tissues that haveimportant roles in energy homeostasis, like the liver and mus-culoskeletal system, as well as the secretion of key metabolicallyactive hormones, primarily through the autonomic nervous sys-tem. The brain is thus able to respond to ongoing as well asunanticipated demands via well-coordinated responses to pre-vent shortfalls in energy stores while maintaining biochemicalhomeostasis. This review focuses on hormonal and related sig-nals that inform the brain of energy levels, thereby influencingenergy intake and ultimately body weight.

As a general rule, signals arising in the periphery that influ-ence food intake and energy expenditure can be partitioned intotwo broad categories (Fig. 1) (1–3). One comprises the signalsgenerated during meals that cause satiation (i.e. feelings of full-

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Copyright © 2008 by The Endocrine Society

doi: 10.1210/jc.2008-1630 Received July 28, 2008. Accepted September 8, 2008.

Abbreviations: AgRP, Agouti-related peptide; apo A-IV, Apolipoprotein A-IV; ARC, arcuatenucleus; CCK, cholecystokinin; DPP-IV, dipeptidyl peptidase IV; GI, gastrointestinal; GLP-1,glucagon-like peptide-1; GLP-1r, GLP-1 receptor; GRP, gastrin-releasing peptide; LHA,lateral hypothalamic area; MC3R, melanocortin 3 receptor; MC4R, melanocortin 4 recep-tor; �MSH, �-melanocyte-stimulating hormone; NMB, neuromedin B; NPY, neuropep-tide-Y; POMC, proopiomelanocortin; PVN, paraventricular nuclei; PYY, peptidetyrosine-tyrosine.

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J Clin Endocrinol Metab, November 2008, 93(11):S37–S50 jcem.endojournals.org S37

ness that contribute to the decision to stop eating) and/or satiety(i.e. prolongation of the interval until hunger or a drive to eatreappears). The prototypical satiation signal is the duodenal pep-tide cholecystokinin (CCK), which is secreted in response to di-etary lipid or protein and which activates receptors on local sen-sory nerves in the duodenum, sending a message to the brain viathe vagus nerve that contributes to satiation. The second cate-gory includes hormones such as insulin and leptin that are se-creted in proportion to the amount of fat in the body. These“adiposity” hormones enter the brain by transport through theblood-brain barrier and interact with specific neuronal receptorsprimarily in the hypothalamus to affect energy balance. Satiationand adiposity signals interact with other factors in the hypothal-amus and elsewhere in the brain to control appetite and bodyweight, and they are the topic of this review.

Body weight (adiposity) is a homeostatically regulated vari-able, and its long-term maintenance can only occur via a closelinkage of energy intake to energy expenditure. This means thatover long intervals, the amount of food consumed must provideenergy equivalent to the amount of energy expended. Humansand most mammals acquire energy in discrete episodes or meals.For many modern-day humans, the impetus to begin a meal israrely if ever based on a biological deficit or need such as insuf-ficient glucose. Rather, “appetite” and “hunger” occur, andmeals are initiated based on habit, time of day, specific socialsituations, convenience, or stress, factors that are not linked toenergy needs and so are nonhomeostatic (4–6). Arguably, this

has been the case throughout human evolution as well, with theinitiation of feeding governed by nonhomeostatic factors such asfood availability or having a safe haven to eat. Thus, the homeo-static influence over food intake is often left to the control overhow many calories are consumed once a meal begins; i.e. on mealsize. Consistent with this, many of the secretions of the gastro-intestinal (GI) tract during a meal, such as CCK, are proportionalto the number of calories consumed, and some of these secretionsfunction as satiation signals to the CNS to help limit meal size (seereviews in Refs. 7–9).

In contrast to satiation signals that are phasically secretedduring meals, adiposity signals are more tonically active, pro-viding an ongoing message to the brain proportional to totalbody fat. Insulin is tonically secreted in basal amounts, withphasic increments occurring during meals, and both componentsof total insulin secretion (i.e. basal and meal-stimulated) are di-rectly proportional to body fat (10). Leptin is secreted in directproportion to body adiposity, following a diurnal pattern withless direct connection to meals than insulin (11). As an individualchanges body weight through caloric restriction or overeating,the amounts of insulin and leptin secreted into the blood changein parallel, and this in turn is reflected as an altered signal of bodyfatness, tantamount to body energy stores, reaching the brain(1–3). These adiposity signals interact with anabolic and cata-bolic neural circuits, causing a change in sensitivity of the brainto satiation signals. For example, during food deprivation ordieting, reduced brain insulin/leptin signaling renders neural cir-

FIG. 1. Model summarizing different levels of control over energy homeostasis. During meals, signals such as CCK, GLP-1, and distension of the stomach that arisefrom the gut (stomach and intestine) trigger nerve impulses in sensory nerves traveling to the hindbrain. These satiation signals synapse with neurons in the nucleus ofthe solitary tract (NTS) where they influence meal size. Ghrelin from the stomach both acts on the vagus nerve and stimulates neurons in the ARC directly. Signalsrelated to body fat content such as leptin and insulin, collectively called adiposity signals, circulate in the blood to the brain. They pass through the blood-brain barrierin the region of the ARC and interact with neurons that synthesize POMC or NPY and AgRP. ARC neurons in turn project to other hypothalamic areas including thePVN and the LHA. The net output of the PVN is catabolic and enhances the potency of satiation signals in the hindbrain. The net output of the LHA, on the other hand,is anabolic, suppressing the activity of the satiation signals. In this way body fat content tends to remain relatively constant over long intervals by means of changes ofmeal size.

S38 Woods and D’Alessio Central Control of Body Weight and Appetite J Clin Endocrinol Metab, November 2008, 93(11):S37–S50

cuits controlling meal size less sensitive to satiation signals suchas CCK. As a consequence, the homeostatic setting is geared forthe intake of larger meals because more food must be consumedbefore a sufficient satiation signal is generated to stop eating.This situation of extra-large meals persists until body weight(and hence the insulin/leptin signal) returns to normal. Con-versely, after excessive weight gain, the increased insulin/leptinbrain signal results in increased sensitivity to satiation signals,and smaller meals are consumed until the excess weight is lost. Amajor dilemma facing clinicians and others involved in publichealth is the slippage in the latter limb of this homeostatic systemthat permits excessive energy storage, obesity, and the associateddiseases of nutritional excess; e.g. diabetes, cardiovascular dis-ease, and some cancers.

Satiation Signals

By definition, satiation factors, when administered to humans oranimals at the start of a meal, result in a smaller-than-normalmeal being consumed. Exogenously administered satiation fac-tors, or endogenous secretion of these compounds, activates spe-cific receptors that cause premature cessation of eating. There areseveral excellent reviews of satiation signals such that only thesalient points need to be reviewed here (7–9, 12–14). It is gen-erally accepted that for an endogenous compound to be consid-ered a satiation signal, it is secreted in response to food ingestion,acts within the time frame of a single meal, reduces meal sizewithout creating malaise or incapacitation, and is effective atphysiological doses, and removing or antagonizing its endoge-nous activity increases meal size (7, 15).

The best-established satiation signals are secreted from spe-cialized enteroendocrine cells in the wall of the GI tract in re-sponse to the digestion and absorption of meals. In the classicmodel of satiation, local sensory nerves express receptors forthese gut peptides as they are secreted such that the brain isimmediately informed about the nutritional content of the mealby monitoring the level of hormones secreted to cope with it. Asa complex meal is consumed, the mix of macronutrients (carbo-hydrates, fats, and proteins) stimulates a proportional blend ofsatiation peptides, and an overall message indicating meal con-tent is integrated in the hindbrain where it activates appropriateresponses, including ultimately cessation of the meal. In humans,this is associated with a sensation of fullness. Although not allintestinal hormones double as satiation signals, they all presum-ably contribute to the assimilation of nutrients; i.e. by stimulat-ing the secretion of appropriate enzymes, water, and other com-pounds into the lumen of the gut and regulating GI motility.Table 1 provides a list of GI and other meal-related hormones/peptides that are generally considered to be satiation signals.

CholecystokininCCK was the compound first identified to fit the criteria for

a satiation factor, so that much is known about its actions. Con-sequently, CCK has become the model for the larger class ofsatiation factors. When food containing fat or protein is con-sumed and enters the duodenum, CCK is secreted from I cells.

CCK enters the blood and has hormonal influences on gut mo-tility, contraction of the gallbladder, pancreatic enzyme secre-tion, gastric emptying, and gastric acid secretion (16–19). How-ever, CCK also diffuses locally to provide a paracrine stimulus toCCK-1 receptors on nearby branches of vagal sensory nerves(20–23). Through this mechanism a message, generally that in-gested fat/protein is being processed and will soon be absorbed,is conveyed to the hindbrain and relayed to the hypothalamuswhere it is integrated into the composite information on energyhomeostasis (20, 24–28) (Fig. 2).

The decrease of meal size elicited by exogenous CCK is dose-dependent, with higher doses causing greater reductions of mealsize. However, CCK does not prevent meals from occurring;rather, it decreases the size of the meal once it has begun, reducinghunger and increasing fullness without concomitant sensationsof illness or malaise. When a CCK-1 receptor antagonist is ad-ministered before the presentation of food to animals or humans,larger-than-normal meals are consumed (29–31), providingcompelling evidence that endogenous CCK normally acts to sup-

TABLE 1. GI hormones that affect satiation

Peptide Effect on food intake

CCK DecreaseGLP-1 DecreasePYY DecreaseApo A-IV DecreaseEnterostatin DecreaseBombesin/GRP/NMB DecreaseOxyntomodulin DecreaseAmylin DecreaseGhrelin Increase

FIG. 2. Satiation signals arising in the GI system converge on the dorsalhindbrain (D) where they are integrated with taste and other inputs. The dorsalhindbrain makes direct connections with the ventral hindbrain (V) where neuralcircuits direct the autonomic nervous system to influence blood glucose andwhere the motor control over eating behavior is located. The dorsal hindbrainalso conveys information on satiation and other factors anteriorly to thehypothalamus and other brain areas. These areas in turn integrate satiation andadiposity signals as well as available nutrients with experience, the social situationand stressors, and with time of day and other factors. The integrated informationis then conveyed posteriorly back to the ventral hindbrain as well as to thepituitary to influence all aspects of energy homeostasis. Animals lacking neuralconnections between the hindbrain and the hypothalamus reduce the intake ofindividual bouts of eating when the stomach is distended or they areadministered CCK. However, those animals cannot regulate their body weightand are not sensitive to past experience, time of day, or social factors (243).


press intake during meals. However, the effect of exogenousCCK is short-lived; the meal-reducing signal does not carry overto a second meal. Moreover, the effect of repeated or chronicadministration of CCK (32, 33) has no effect on body weightbecause the short-term regulation of meal size is overridden byoverall energy balance. That is, in the context of lower adiposity,leptin and insulin signals to the brain are reduced and satiationfactors like CCK have a reduced effect to restrict meal size.

There is strong experimental evidence supporting a role forCCK as a satiation factor in humans. CCK levels increase aftermeals, and infusion of an exogenous CCK-1 receptor agonist,CCK-33, to postprandial levels suppresses food intake (34, 35).Furthermore, infusion of a CCK-1 receptor antagonist to healthyhumans causes an increase in caloric intake, strongly implicatingendogenous CCK as a brake on meal size (29, 36). The effects ofCCK-1 agonism and antagonism are similar in lean and obesehumans and are associated with appropriate changes in hungerand fullness. Interestingly, blockade of CCK-1 receptors affectsthe postprandial responses of other GI hormones, attenuatingthe usual rise in peptide YY (PYY) and abolishing the suppres-sion of ghrelin (37). This latter finding suggests that beyonddirectly inhibiting food intake, CCK acts as a proximal mediatorof the broader satiation process. Two minor single nucleotidepolymorphisms in the CCK-1 receptor gene promoter have beenassociated with increased body fatness, but the mechanism ofthis association has not been explained (38).

Glucagon-like peptide-1Glucagon-like peptide-1 (GLP-1) is derived from progluca-

gon in intestinal L cells that are most prevalent in the ileum andcolon (39). GLP-1 secretion is elicited by nutrients, but the mech-anism whereby the distal L cells are stimulated early within mealsmay require neurohumoral signals initiated in the proximal re-gions of the small intestine (40). GLP-1 has a broad range ofactions on glucose metabolism (41), most prominently stimula-tion of insulin secretion, but also inhibition of glucagon release.Because GLP-1 inhibits GI motility and secretions, it has beenimplicated as a major component of the “ileal brake,” an inhib-itory feedback mechanism that regulates transit of nutrientsthrough the course of the GI tract (42, 43). It has generally beenassumed that GLP-1 mediates these various actions through anendocrine mechanism, by binding directly to key target tissueslike pancreatic islet cells. However, this mechanism has recentlybeen called into question, in large part because GLP-1 is rapidlymetabolized in the circulation by the protease dipeptidyl pepti-dase IV (DPP-IV) (44). Indeed, the half-life of GLP-1 in humanplasma is only 1–2 min, and the product of DPP-IV action, atruncated GLP-1, is inactive with regard to glucose metabolism(45). Because the GLP-1 receptor (GLP-1r) is expressed by pe-ripheral and CNS neurons as well as by cells in the pancreaticislets and the GI tract, recent attention has focused on neuralmechanisms of GLP-1 action (46–48).

GLP-1 administration reduces food intake in animals andhumans (49–54), and these anorectic actions are thought to bemediated through both peripheral and central mechanisms. Apopulation of neurons that synthesize GLP-1 is located in thebrain stem and projects to hypothalamic and brain stem areas

important in the control of energy homeostasis (55, 56). Cen-trally administered GLP-1 reduces food intake through at leasttwo mechanisms. GLP-1r in the hypothalamus appear to reduceintake by acting on caloric homeostatic circuits (57–60),whereas GLP-1r in the amygdala reduce food intake by elicitingsymptoms of stress or malaise (61, 62).

Systemically administered GLP-1 elicits satiation in healthy(53), obese (63), and diabetic (64, 65) humans. Because the half-life of active GLP-1 is less than 2 min, any direct effects are likelytransient, and the reduction of food intake may result from in-hibitory effects of GLP-1 on GI transit and reduced gastric emp-tying (66). However, peripherally administered GLP-1 doescross the blood-brain barrier (67), perhaps enabling circulatingGLP-1 to interact with the brain GLP-1r. Because it both reducesfood intake and stimulates insulin secretion, the GLP-1 systemhas been adapted to the treatment of type 2 diabetes (68, 69).DPP-IV-resistant, long-acting GLP-1r agonists are effective atreducing blood glucose in persons with type 2 diabetes and alsocause weight loss (70). In addition, inhibitors of DPP-IV, whichelevate endogenous GLP-1 levels, are also effective at improvingglycemic control in diabetic patients (71, 72).

The effect of chronic GLP-1r agonists to cause weight loss isnot consistent with the general principle that satiation peptidesare subservient to long-term regulators of energy balance, suchas leptin (3). One potential explanation is that because GLP-1can activate nonhomeostatic pathways that suppress food intakeand otherwise reduce body weight, the effects of chronic admin-istration of GLP-1r agonists work around the homeostatic sys-tems controlling body weight. Indeed, nausea, a hallmark featureof nonhomeostatic anorexia, is very common with GLP-1r ag-onist treatment (73), although this response wanes with contin-ued treatment and is not present in all persons who lose weight.Another possible explanation for why patients treated with in-dictable GLP-1r agonists lose weight is that repeated pharma-cological doses of a satiation signal can overcome homeostaticrestraints. Consistent with this hypothesis is the failure ofDPP-IV inhibitor treatment, which has a smaller effect to raisecirculating concentrations of GLP-1r agonist activity than doinjectable GLP-1 mimetics to cause weight loss. Although it is notyet clear how GLP-1r agonists cause weight loss, the fact thatthey do challenges the current model of the interaction of sati-ation factors with overall energy homeostasis.

Glicentin, GLP-2, oxyntomodulin, and glucagonOther peptides derived from the processing of proglucagon

include glicentin, GLP-2, and oxyntomodulin, as well as gluca-gon itself (39). Glicentin inhibits gastric acid secretion (74), butat least in rats, does not affect food intake (75). In contrast,oxyntomodulin, a C-terminally extended congener of glucagon,does reduce food intake in animals when given centrally or pe-ripherally (75, 76). Although a unique receptor for oxyntomodu-lin has yet to be identified, oxyntomodulin may exert its ano-rectic effect through the GLP-1r because subthreshold doses ofthe GLP-1r antagonist, exendin (9–39), block both GLP-1 andoxyntomodulin-induced reductions in food intake (75). Oxyn-tomodulin is thought to cross the blood-brain barrier and stim-ulate neurons in the arcuate nucleus (ARC) that express GLP-1r


and control energy homeostasis (77, 78). Long-term treatmentwith oxyntomodulin causes a persistent decrease in food intakeand attenuated weight gain in rats (79). Interestingly, weight lossin animals given oxyntomodulin chronically is greater than whatwould be anticipated from reduced caloric intake (78), suggest-ing additional effects on energy expenditure.

Short-term treatment with iv oxyntomodulin decreases hun-ger, reduces consumption of an ad libitum meal, and has ananorectic action that persists for 12 h after cessation of treatmentin lean humans (80). Moreover, in obese subjects randomized toinjections of oxyntomodulin or placebo before each meal for 4wk, there was a significant loss of weight associated with activetreatment. Oxyntomodulin caused an approximately 0.5 kg/wkreduction in body weight and was generally well tolerated. Thesefindings suggest that at least two proglucagon products may havea role in the regulation of food intake. Distinguishing betweenthe effects of GLP-1 and oxyntomodulin, in particular the rela-tive in vivo actions on the GLP-1r, is an important next step inapplying these compounds to clinical medicine.

GLP-2 acts through a specific GLP-2 receptor to stimulateintestinal mucosal growth and has become the focus of researchon short-bowel syndrome (81, 82). GLP-2 and GLP-1 havenearly 50% sequence homology and are secreted in parallel fromperfused ileal preparations (83). Intracranial administration ofGLP-2 reduces food intake in rats, and the effect can be blockedwith a specific GLP-1r antagonist (84). More recent studies inhumans found no effect of iv GLP-2 on food intake (85).

Glucagon is the most widely studied hormone cleaved frompreproglucagon (39). It is secreted from both pancreatic A cellsand probably also in small amounts from the distal intestine. Thebest known action of glucagon is to increase hepatic glucoseproduction by stimulating glycogenolysis and gluconeogenesis.Glucagon also reduces meal size when administered systemically(86, 87), but not centrally (88), the signal being detected in theliver and relayed to the brain (89). A role for glucagon in thenormal control of meal size was demonstrated by the observationthat blocking endogenous glucagon action in rats increases foodintake (90, 91). There is little convincing evidence that glucagonplays a role in food intake in healthy humans.

Peptide tyrosine-tyrosine (PYY)PYY is a member of a family of homologous peptides that also

includes pancreatic polypeptide and neuropeptide-Y (NPY).Like proglucagon-derived peptides, PYY is synthesized and se-creted by L cells in the distal ileum and colon (92). PYY is secretedas PYY (1–36) and is metabolized to PYY (3–36) by DPP-IV (93,94). Receptors that mediate the effects of PYY, including reduc-tion of food intake, belong to the NPY receptor family and in-clude Y1, Y2, Y4, and Y5 (95). However, PYY (3–36) is a highlyselective agonist activity for the Y2 receptor, and it also reducesfood intake in humans and animals (96, 97). Like GLP-1, PYYhas been implicated in GI motility and is considered a majorcomponent of the ileal brake (98, 99). Secretion of PYY is stim-ulated by food intake (100) and also by the presence of nutrientswithin the ileum itself (101); lipid seems to be a particularlyeffective stimulus. Similar to the case with GLP-1, it is not clearwhether PYY release requires direct nutrient contact with L cells,

or if neurohumoral signals originating from the more proximalGI tract mediate the response. There is evidence that PYY influ-ences food intake through its interaction with Y2 receptors in theARC because it freely crosses the blood-brain barrier (102) andbecause systemic PYY (3–36) is ineffective in reducing food in-take in the Y2-deficient mouse (103).

Studies in humans have demonstrated that PYY signaling re-duces food intake and that abnormalities in this system arepresent in obese subjects. PYY secretion is proportional to thecaloric content of meals, with larger meals eliciting a significantlylarger response (104, 105). Fasting and postprandial levels ofPYY are lower in obese adults compared with lean controls (105,106). The attenuated rise in PYY after eating has also been ob-served in obese adolescents (107). Infusion of PYY (3–36) intolean and obese humans reduced food consumption measuredduring test meals (104–106), although there remains some ques-tion as to whether this effect of PYY (3–36) is pharmacologicalor occurs at circulating levels seen after eating. Obese subjects didnot differ in their sensitivity to PYY, and there was no differencein the relative PYY (1–36) and PYY (3–36) levels after exogenousadministration. Taken together, these findings suggest that ab-normal PYY production, rather than anorectic action of metab-olism, could contribute to obesity.

Interestingly, there is evidence that genetic variations in thePYY and Y2 sequences are associated with body weight. A com-mon gene polymorphism in the Y2 receptor has been associatedwith a reduced likelihood of obesity in a cohort study of men witha broad range of BMI (108). Additionally, in a survey of lean andvery obese men, a polymorphism in the PYY allele was found tosegregate with increased body weight; this genetic variant of PYYwas also found to have reduced binding to its receptor and anattenuated anorectic effect in mice (109). In total, the data col-lected in human studies support a role for PYY in the regulationof food intake and build the strongest case for any of the satiationfactors in the pathogenesis of obesity.

Apolipoprotein A-IVApolipoprotein A-IV (apo A-IV) is synthesized by intestinal

mucosal cells during the packaging of digested lipids into chy-lomicrons that subsequently enter the blood via the lymphaticsystem (110). Apo A-IV is also synthesized in the ARC (111).Systemic or central administration of apo A-IV reduces foodintake and body weight of rats (112), and administration of apoA-IV antibodies increases food intake (113). Apo A-IV appearsto work by interacting with the CCK signal (114). Because bothintestinal and hypothalamic apo A-IV are regulated by absorp-tion of lipid but not carbohydrate (115), this peptide may be animportant link between short- and long-term regulators of bodyfat (see review by Tso and Liu in Ref. 116).

EnterostatinA second digestion-related peptide, enterostatin, is also

closely tied to intestinal processing of lipid. The exocrine pan-creas secretes lipase and colipase to aid in the digestion of fat, andenterostatin, a pentapeptide, is cleaved from colipase in the in-testinal lumen and enters the circulation. Administration of ex-ogenous enterostatin either systemically (117, 118) or directly


into the brain (119) reduces food intake, and, when rats are givena choice of foods, the reduction is specific for fats; that is, en-terostatin does not decrease the intake of carbohydrate or pro-tein (120). Therefore, two peptides that are secreted from the gutduring the digestion and absorption of lipids, apo A-IV and en-terostatin, act as signals that decrease food intake, and at leastone of them selectively reduces the intake of fat. Macronutrientspecificity has not been assessed with apo A-IV. There are no datafrom human studies to confirm the findings with apo A-IV andenterostatin on food intake.

Bombesin-family peptidesMembers of the bombesin family of peptides including bomb-

esin itself (an amphibian peptide) and its mammalian analogs,gastrin-releasing peptide (GRP) and neuromedin B (NMB), re-duce food intake when administered systemically in humans andanimals or into the CNS of animals (121–123). Consistent withthe possibility that these peptides act endogenously to reducefood intake, mice deficient for the GRP receptor eat significantlylarger meals and develop late-onset obesity (124). Whereas mostsatiation factors act by reducing the size of an ongoing meal (4),bombesin peptides are an interesting exception in that when theyare administered between meals, they increase the amount oftime until the subsequent meal begins; i.e. they increase satiety aswell as satiation (125, 126).

Both bombesin and GRP reduce food intake when infusedinto human subjects (127, 128). Antagonism of endogenousbombesin receptors has demonstrable effects on gastric, intesti-nal, and gallbladder function but has not been studied with re-gard to food intake (129, 130). Therefore the case for GRP as aphysiological mediator of satiation in humans is not as strong asfor CCK.

AmylinAmylin (also called islet amyloid polypeptide) is a peptide

hormone secreted by pancreatic B cells in tandem with insulinsecretion, which inhibits gastric emptying and gastric acid se-cretion, lowers glucagon concentrations, and reduces food in-take (131). Amylin causes a dose-dependent reduction of mealsize when administered systemically or directly into the brain(132–136), and antagonism of amylin action in the CNS causesincreased food intake and body weight (137). Consistent withthis, targeted deletion of the amylin gene causes increased bodyweight in mice.

Amylin signals through the calcitonin receptor when it hasbeen modified by receptor activity modifying proteins (138,139), and in contrast to many satiation peptides that reduce foodintake by stimulating the visceral afferent nerves, amylin seemsto act as a hormone, directly stimulating neurons in the areapostrema in the hindbrain (133, 140). In fact, the anorectic ac-tion of amylin shares features with both satiation signals (phasic,meal-induced secretion) and adiposity signals (chronic interrup-tion of action in rodents causes increased body fatness). Amylinseems to interact with both types of regulation in that the abilityof amylin to reduce meal size is augmented when brain insulinaction is elevated (141) and the effects of CCK and bombesin aremuted in the absence of amylin signaling (142).

Amylin has been developed as a therapeutic, with the syn-thetic analog pramlintide now available for the treatment of type1 and type 2 diabetes and clinical trials under way to determinethe efficacy in treating obesity. In diabetic patients treated withpramlintide for 1 yr, weight loss averaged approximately 2 kgrelative to placebo-treated controls (143, 144). Similar to treat-ment with the GLP-1r agonist exendin-4, pramlintide presentssupraphysiological levels of amylin-like activity to patients, andthe primary side effect is nausea. Nonetheless, the clinical expe-rience with pramlintide supports the idea that chronic activity ofa satiating compound can cause weight loss.

GhrelinGhrelin, a product of specific endocrine cells in the stomach

and duodenum, actually stimulates food intake and is the mostpotent known circulating orexigen (145). Ghrelin is secretedfrom the fundic region of the stomach and has been identified asthe endogenous ligand for the GH secretagogue receptor. Fastingincreases plasma ghrelin (146), and exogenous ghrelin increasesfood intake when administered peripherally or centrally (147–149). Ghrelin has also been linked to the anticipatory aspects ofmeal ingestion because levels peak shortly before scheduledmeals in humans and rats (150) and fall shortly after meals end.Moreover, elevated ghrelin has been linked to the hyperphagiaand obesity of individuals with the Prader-Willi syndrome (151).Ghrelin is also unique among the GI signals in that its messageappears to be conveyed directly to receptors in the hypothalamus(152–155), although, as is the case for CCK, GLP-1, and otherGI signals, there are ghrelin receptors on vagal sensory nerves(156) but they do not appear to signal satiation (157).

Satiation signals: summary of general principlesSatiation appears to be a complex phenomenon, mediated by

a number of GI peptides. Although it is clear that the differentsatiation factors respond to specific nutrient stimuli (e.g. CCK toprotein and fat, GLP-1 to carbohydrate and fat, PYY primarilyto fat, and so on), it has not been proven that mixed meals ofdiffering macronutrient content elicit the release of distinct cock-tails of GI hormones. However, given the wide range of specificfactors that seem to mediate satiation, it is logical to presume thatthis process is subject to highly refined regulation. Especiallyimportant is the modulation of the action of satiation by factorssuch as leptin and insulin that are responsive to body adiposity.This interaction is the critical site of endocrine regulation ofeating and energy homeostasis.

A key feature of the system regulating food intake is that mostif not all of the peptides that are made in the GI tract and influencesatiation are also synthesized in the brain. This includes CCK,GLP-1, GLP-2, oxyntomodulin, apo A-IV, GRP, NMB, PYY,and ghrelin. Exceptions are the pancreatic hormones that influ-ence energy homeostasis (i.e. insulin, glucagon, and amylin) andthe adipose tissue/stomach hormone leptin; and each of theselatter hormones has long-term effects on body fat as well. Thefact that so many peripheral signals that influence food intake arealso synthesized locally in the brain raises the question ofwhether and how the same signals secreted from different placesin the body interact. A simple generalization is that, if a peptide


reduces (or increases) food intake when administered systemi-cally, it probably has the same action when administered cen-trally. With regard to changes of food intake, this is true of CCK,GLP-1, apo A-IV, GRP, NMB, PYY, and ghrelin. Interestingly,it is also generally true that peptide signals that are not synthe-sized in the brain nonetheless have the same effect on food intakewhen administered directly into the brain. This is true of leptin,insulin, and amylin, but not glucagon.

It is worth contemplating why there is such a large imbalanceamong GI hormones that suppress and stimulate food intake; i.e.whereas numerous peptides secreted from the stomach and in-testines decrease food intake, only one known factor, ghrelin,increases it. One possibility relates to the phenomenon of sati-ation itself and the benefits of meal termination. Meals end longbefore any physical limit of the stomach is reached. This is easilydemonstrated when food is diluted with noncaloric bulk andanimals increase the volume of food consumed to attain theirnormal caloric load (158, 159). It has therefore been argued thata primary function of satiation signals is to prevent the consump-tion of too many calories at one time, lest the influx of nutrientsand substrates overwhelm the capacity of the animal to maintainhomeostasis (5, 160). That is, an important role of the GI tractis to analyze and respond to the incoming macronutrients whilea meal is being eaten, helping to preempt excessive challenges tobiochemical homeostasis. A corollary to this role for satiationsignals is that adequate food intake does not require much spe-cific stimulation, only the absence of inhibitory signals for foodintake combined with the presence of food. Until recently therewas some question as to whether manipulation of meal size byfactors activating the satiation system could have therapeuticefficacy for weight reduction. One possibility was that becausethe effects of satiation peptides are dependent on body adiposity,their action would become muted as food intake decreaseddue to homeostatic regulation of body energy stores. Evidencefor this was demonstrated for the satiating action of CCK ingenetically obese Zucker rats (161, 162), but not for rats ren-dered obese by lesions of the ventromedial hypothalamus (163).Furthermore, rats genetically prone to becoming obese when feda high-fat diet (diet-induced obesity rats) are actually more sen-sitive to the satiating action of CCK both before and after be-coming obese (164). Some strains of genetically obese mice arecomparably as sensitive as lean controls (165), and CCK workswell in obese humans when administered iv (166). Hence, thereis no general principle with regard to sensitivity in obesity, atleast with regard to CCK. There is evidence that the satiatingaction of GLP-1 is leptin-dependent (167). All of these observa-tions were made with animals having relatively free access totheir diets so that they could vary their meal patterns in theservice of maintaining body fat; i.e. when individuals are con-strained to eating only small meals, they compensate by eatingmore often, thereby maintaining daily caloric intake and bodyweight. This has been observed when CCK is administered be-fore every meal in experimental animals; animals receiving thistreatment eat smaller and more frequent meals while keepingbody weight constant (33, 168). In contrast, if animals are con-strained to eating only three meals a day and receive a satiatingpeptide at each mealtime, they cannot compensate and conse-

quently lose weight (169). The advent of long-acting formula-tions of GLP-1 and amylin, peptides that seem to have a role insatiation (170, 171), has resulted in weight loss (172, 173). How-ever, at present it is not clear that the chronic effects of GLP-1 andamylin receptor agonists are entirely due to continued hypopha-gia as opposed to other, nonbehavioral actions of the com-pounds.Understandinghowachronicpharmacological stimulusto the satiation system lowers body weight is important for re-fining the models for normal energy homeostasis.

Adiposity Signals

Insulin from the pancreatic B cells and leptin from white adipo-cytes (as well as the stomach and other tissues) are each secretedin direct proportion to body fat. Both hormones are transportedthrough the blood-brain barrier (174, 175) and gain access toneurons in the hypothalamus and elsewhere in the brain to in-fluence energy homeostasis. Hence, neurons sensitive to insulinand/or leptin receive a signal directly proportional to the amountof fat in the body. Consistent with this, if exogenous insulin orleptin is added locally into the brain, the individual responds asif excess fat exists in the body; i.e. food intake is reduced andbody weight is lost. Analogously, if either the leptin or the insulinsignal is reduced locally in the brain, the individual responds asif insufficient fat is present in the body, more food is eaten, andthe individual gains weight. There are many reviews of thesephenomena (1, 2, 87, 176–178).

An important distinction is that whereas satiation signals pri-marily influence how many calories are eaten during individualmeals, adiposity signals are more directly related to how much fatthe body carries and maintains. Developing novel compoundsthat interact directly with the normal detection of and responseto adiposity signals would therefore seem a more promising ther-apeutic approach for obesity. A key question therefore is whetheragonists for the leptin and/or insulin receptor would be viabletargets for the pharmaceutical industry. One obstacle is that tobe effective, any compound would have to gain access to keyreceptors in the brain, yet any such compound would most likelyhave to be administered systemically. Administering insulin sys-temically elicits hypoglycemia and other side effects, and hypo-glycemia per se increases food intake (179–181), thus workingagainst the therapeutic intent. Systemically administered insulindoes result in reduced food intake when plasma glucose is pre-vented from decreasing in animal models (182, 183), but thiswould be difficult to achieve therapeutically. Alternatively, thereare reports that some formulations of nasally administered in-sulin elicit reduced food intake and body weight in humans with-out altering plasma glucose (184, 185).

Leptin does not have the same counterproductive systemiceffects as insulin, and in fact improves insulin sensitivity andcirculating lipoprotein concentrations in subjects with metabolicabnormalities associated with anti-HIV treatment (186). More-over, chronic leptin treatment of patients with generalized lipo-dystrophy causes significant improvements of insulin resistance,hypertriglyceridemia, hepatic steatosis, and glucose metabolism(187), responses found across the spectrum of lipodystrophies.


However, the results of clinical trials using leptin in healthy obesesubjects have been variable, with significant weight loss, but notof a remarkable magnitude, and some bothersome side effectsrelated to peptide administration.

Insulin and leptin resistance characterize the obese state,meaning that more of each hormone is required to achieve aparticular physiological effect than occurs in lean individuals.Individuals with diabetes cannot achieve a maximum insulinresponse because of defects in insulin secretion and insulin ac-tion. The insulin and leptin resistance that characterizes periph-eral tissues in obesity is also manifested in the brain. For onething, the transport of both hormones from the blood to the brainis compromised in obesity such that less signal reaches criticalneurons (188–190), and the ability of those neurons to respondis also compromised. When insulin is administered locally intothe brain near the hypothalamus, both genetically obese (191)and dietary obese individuals (192) have a reduced or absentreduction of food intake, and this is the case for leptin as well(193). Hence, an inability on the part of the brain to respond tosignals indicating that there is excess fat in the body may be acontributing and/or confounding factor in obesity. An insulinmimetic that interacts with the insulin receptor and is efficaciouswhen given orally or directly into the brain has been reported toreduce food intake and body weight in obese rodents (194, 195),but it evidently has problematic side effects.

Central Integrating Circuits

Although receptors for insulin and leptin are found in severaldiscrete areas throughout the brain, many that are especiallyimportant for controlling energy homeostasis are localized in theARC of the hypothalamus (Fig. 1). The ARC is ideally suited asa receptor site for body adiposity as well as for integration ofdiverse hormonal and neural signals because there is evidencethat blood-borne molecules have relatively greater access to re-ceptors there than to other brain areas, and this is thought to bedue in part to a relatively leaky blood-brain barrier in the ARC(196, 197). Two categories of ARC neurons are particularly im-portant. One synthesizes the prepropeptide, proopiomelanocor-tin (POMC), and in the ARC POMC is cleaved to �-melanocyte-stimulating hormone (�MSH) as a neurotransmitter. �MSH actsat melanocortin 3 and melanocortin 4 receptors (MC3R andMC4R) on neurons in other hypothalamic areas and elsewherein the brain to reduce food intake, and synthetic agonists forMC3R/MC4R are available that cause hypophagia andweight loss in experimental animals (see reviews in Refs. 1, 2,196, and 198 –202). The catabolic action of both leptin andinsulin relies upon �MSH signaling because administration ofantagonists to MC3R/MC4R blocks each of their actions inthe brain (203, 204).

The second group of ARC neurons synthesizes and secretestwo neuropeptides important in energy homeostasis, and theiraxons project to many of the same brain areas as POMC neurons.Agouti-related peptide (AgRP) is an antagonist at MC3R andMC4R (199) such that one action of these neurons is to counterthe activity of POMC neurons. NPY acts at Y receptors to stim-

ulate food intake (205–207). When either AgRP or NPY is ad-ministered chronically into the brain, body weight increases(202, 208–211). In fact, when a single dose of AgRP is admin-istered into the brain near the ARC, food intake is increased for1 wk or more (212, 213). Insulin and leptin each have a net effectto suppress the activity of NPY/AgRP neurons in the ARC.

The POMC and NPY/AgRP neurons in the ARC share manyimportant features. Each is the origin of tracts projecting to otherhypothalamic and brain areas, the two tracts often occurring inparallel. The POMC-originating tract has an overall cataboliceffect such that when it is more active food intake is reduced,energy expenditure is increased, and if prolonged,body fat is lost.Conversely, the NPY/AgRP-originating tract is anabolic, withheightened activity causing more food to be ingested and body fatto increase. Under normal conditions, both circuits are activesuch that a change of input that is either stimulatory or inhibitoryto either type of neuron elicits rapid changes of many energeticparameters. In the acute situation, both food intake and plasmaglucose are altered because the ARC influences circuits project-ing to behavioral sites as well as autonomic circuits influencinghepatic glucose secretion and pancreatic insulin secretion(214–216).

Another important aspect of the area including the ARC andnearby hypothalamic nuclei is that receptors for many of thesatiation signals discussed above are expressed there; i.e. circu-lating ghrelin is thought to interact directly with ARC neurons(152), which are also directly or indirectly sensitive to changes ofCCK, GLP-1, NMB, and apo A-IV. Because most of these pep-tides are made within the brain, the origin of molecules alteringARC activity may not be directly from the plasma as occurs withinsulin, leptin, and ghrelin. Numerous circuits from the hind-brain satiation area and elsewhere in the brain project to theregion of the ARC (25, 27, 217). Finally, ARC neurons are alsosensitive to local levels of energy-rich nutrients, including glucose(218), some long-chain fatty acids �e.g. oleic acid (219, 220)�,and some amino acids �e.g. leucine (221)�.

Thus, the ARC is situated to be sensitive to a wide array ofsignals important in energy regulation (216, 222–224). It is di-rectly sensitive to hormones whose secretion is proportional tobody fat (insulin and leptin); it receives information on ongoingmeals either directly or indirectly; and it is sensitive to local levelsof nutrients. Importantly, numerous neuronal circuits intercon-nect the ARC and nearby hypothalamic areas with the nucleus ofthe solitary tract, enabling the hypothalamic homeostatic net-work to be constantly aware of ongoing GI activity while at thesame time influencing brain stem autonomic areas projecting tothe GI tract, liver, pancreas, and other tissues (25, 27, 225–227).The ARC can therefore be considered as a key afferent as well asefferent area for the regulation of energy homeostasis.

Although ARC neurons project throughout the brain, twonearby target areas are thought to be especially important. Theparaventricular nuclei (PVN) express both MC3R/MC4R andvarious Y receptors, and PVN neurons in turn synthesize andsecrete neuropeptides that have a net catabolic action, includingCRH and oxytocin. Administration of exogenous CRH (228) oroxytocin (229) into the brain reduces food intake. Hence, a cat-abolic circuit exists in which an increase of body fat is associated


with increased insulin and leptin, increased �MSH, and de-creased NPY and AgRP activity, and consequently increased ac-tivity of CRH, oxytocin, and other catabolic signals; all of theselead in turn to reduced food intake and increased energyexpenditure.

The lateral hypothalamic area (LHA) has a contrasting profilefrom the PVN (230). It also receives direct inputs from the ARC,and it contains neurons that synthesize and secrete anabolic pep-tides, including melanin-concentrating hormone and the orex-ins. Administration of melanin-concentrating hormone (231,232) or orexin agonists (233) increases food intake and bodyweight gain. The architecture and functioning of these opposinghypothalamic circuits therefore enables rapid and fine-tunedcontrol over energy homeostasis because the brain can simulta-neously turn up one system (e.g. catabolic or anabolic) whileturning down the other.

Integration of Satiation and Adiposity Signals

Total food intake each day is the sum of the intake in individualmeals (including snacks). As discussed above, the time that mealsare initiated is often under the control of nonhomeostatic influ-ences (4, 5, 160, 234). Hence, whatever regulatory control existsfor body weight must be exerted on how much is eaten in indi-vidual meals, and meal termination is consequently under theinfluence of satiation signals. The efficacy of satiation signals toterminate a meal varies with the amount of fat in the body assignaled to the brain by leptin and insulin. When an individualhas been food restricted (or been on a diet) and loses weight,leptin and insulin secretion both decline, and a reduced adipositysignal reaches the ARC. This in turn lowers sensitivity to satia-tion signals such as CCK, and the consequence is that more foodis eaten during meals before satiation or feeling full occurs. Con-versely, individuals who have overeaten and gained weight haveelevated levels of adiposity signals and enhanced sensitivity tosatiation signals, reducing the trajectory of weight gain or evenpromoting weight loss. When low doses of leptin or insulin areinfused directly into the brain near the ARC, they greatly enhancethe ability of satiation signals to reduce food intake �e.g. muchless CCK or other satiation signals is required to terminate a meal(235–241)�, andwhen theadiposity signal in thebrain is reduced,satiation signals are less efficacious (242).

Conclusion

The brain receives and integrates diverse information pertinentto the maintenance of energy homeostasis. Adiposity signals suchas insulin and leptin act in the arcuate nuclei to provide a back-ground tone, and this tone in turn determines the sensitivity ofthe brain to satiation signals influencing how much food is eatenat any one time. It is important to recognize that this “homeo-static” mechanism provides at most a background influence, andthat it only subtly influences intake during any given meal. Thisis because social factors, palatability, habits, the presence ofpredators, stress, and many other factors are also always at work,

influencing not only when meals occur but how much food isconsumed as well. Only when extraneous factors are tightly con-trolled in laboratory animal experiments, or else when ingestionis precisely monitored and quantified over periods of days orweeks in free-feeding humans, do the effects of these homeostaticsignals become apparent.

Acknowledgments

Address all correspondence and requests for reprints to: Stephen C.Woods, Department of Psychiatry, University of Cincinnati, 2170East Galbraith Road, Cincinnati, Ohio 45237. E-mail: [email protected].

This work was supported by National Institutes of Health AwardsDK 17844 and DK 57900.

Disclosure Summary: S.C.W. received lecture fees from Sanofi-Aven-tis and from Merck. D.A.D. received lecture fees from Merck, Takeda,and MannKind.

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