Departments of Psychiatry (S.C.W.) and Medicine (D.A.D.), University of Cincinnati, Cincinnati, Ohio 45237
Address all correspondence and requests for reprints to: Stephen C. Woods, Department of Psychiatry, University of Cincinnati, 2170 East Galbraith Road, Cincinnati, Ohio 45237. E-mail: steve.woods{at}psychiatry.uc.edu.
Context: Energy balance is critical for survival and health,and control of food intake is an integral part of this process.This report reviews hormonal signals that influence food intakeand their clinical applications.
Evidence Acquisition: A relatively novel insight is that satiationsignals that control meal size and adiposity signals that signifythe amount of body fat are distinct and interact in the hypothalamusand elsewhere to control energy homeostasis. This review focusesupon recent literature addressing the integration of satiationand adiposity signals and therapeutic implications for treatmentof obesity.
Evidence Synthesis: During meals, signals such as cholecystokininarise primarily from the GI tract to cause satiation and mealtermination; signals secreted in proportion to body fat suchas insulin and leptin interact with satiation signals and provideeffective regulation by dictating meal size to amounts thatare appropriate for body fatness, or stored energy. Althoughsatiation and adiposity signals are myriad and redundant andreduce food intake, there are few known orexigenic signals;thus, initiation of meals is not subject to the degree of homeostaticregulation that cessation of eating is. There are now drugsavailable that act through receptors for satiation factors andwhich cause weight loss, demonstrating that this system is amenableto manipulation for therapeutic goals.
Conclusions: Although progress on effective medical therapiesfor obesity has been relatively slow in coming, advances inunderstanding the central regulation of food intake may ultimatelybe turned into useful treatment options.
The past decade has seen an increasing recognition that a complexinterplay exists between the central nervous system (CNS) andthe activity of numerous organs involved in energy homeostasis.This requires the transmission of key information to the brain,and control of food intake is one component of energy balancewhere endocrine signaling from the periphery to the CNS hasa particularly important role. Considered broadly, energy homeostasisconsists of the interrelated processes integrated by the brainto maintain energy stores at appropriate levels for given environmentalconditions. Energy homeostasis thus includes the regulationof nutrient levels in key storage organs (e.g. fat in adiposetissue and glycogen in the liver and elsewhere) as well as inthe blood (e.g. blood glucose). To accomplish this, the brainreceives continuous information about energy stores and fluxesin critical organs, about food that is being eaten and absorbed,and about basal and situational energy needs by tissues. Thebrain in turn controls tissues that have important roles inenergy homeostasis, like the liver and musculoskeletal system,as well as the secretion of key metabolically active hormones,primarily through the autonomic nervous system. The brain isthus able to respond to ongoing as well as unanticipated demandsvia well-coordinated responses to prevent shortfalls in energystores while maintaining biochemical homeostasis. This reviewfocuses on hormonal and related signals that inform the brainof energy levels, thereby influencing energy intake and ultimatelybody weight.
As a general rule, signals arising in the periphery that influencefood intake and energy expenditure can be partitioned into twobroad categories (Fig. 1) (1, 2, 3). One comprises the signalsgenerated during meals that cause satiation (i.e. feelings offullness that contribute to the decision to stop eating) and/orsatiety (i.e. prolongation of the interval until hunger or adrive to eat reappears). The prototypical satiation signal isthe duodenal peptide cholecystokinin (CCK), which is secretedin response to dietary lipid or protein and which activatesreceptors on local sensory nerves in the duodenum, sending amessage to the brain via the vagus nerve that contributes tosatiation. The second category includes hormones such as insulinand leptin that are secreted in proportion to the amount offat in the body. These "adiposity" hormones enter the brainby transport through the blood-brain barrier and interact withspecific neuronal receptors primarily in the hypothalamus toaffect energy balance. Satiation and adiposity signals interactwith other factors in the hypothalamus and elsewhere in thebrain to control appetite and body weight, and they are thetopic of this review.
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 arise from the gut (stomach and intestine) trigger nerve impulses in sensory nerves traveling to the hindbrain. These satiation signals synapse with neurons in the nucleus of the 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. Signals related 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 barrier in 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 the PVN 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 of meal size.
Body weight (adiposity) is a homeostatically regulated variable,and its long-term maintenance can only occur via a close linkageof energy intake to energy expenditure. This means that overlong intervals, the amount of food consumed must provide energyequivalent to the amount of energy expended. Humans and mostmammals acquire energy in discrete episodes or meals. For manymodern-day humans, the impetus to begin a meal is rarely ifever based on a biological deficit or need such as insufficientglucose. Rather, "appetite" and "hunger" occur, and meals areinitiated based on habit, time of day, specific social situations,convenience, or stress, factors that are not linked to energyneeds and so are nonhomeostatic (4, 5, 6). Arguably, this hasbeen the case throughout human evolution as well, with the initiationof feeding governed by nonhomeostatic factors such as food availabilityor having a safe haven to eat. Thus, the homeostatic influenceover food intake is often left to the control over how manycalories are consumed once a meal begins; i.e. on meal size.Consistent with this, many of the secretions of the gastrointestinal(GI) tract during a meal, such as CCK, are proportional to thenumber of calories consumed, and some of these secretions functionas satiation signals to the CNS to help limit meal size (seereviews in Refs. 7, 8, 9).
In contrast to satiation signals that are phasically secretedduring meals, adiposity signals are more tonically active, providingan ongoing message to the brain proportional to total body fat.Insulin is tonically secreted in basal amounts, with phasicincrements occurring during meals, and both components of totalinsulin secretion (i.e. basal and meal-stimulated) are directlyproportional 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 signalof body fatness, tantamount to body energy stores, reachingthe brain (1, 2, 3). These adiposity signals interact with anabolicand catabolic neural circuits, causing a change in sensitivityof the brain to satiation signals. For example, during fooddeprivation or dieting, reduced brain insulin/leptin signalingrenders neural circuits controlling meal size less sensitiveto satiation signals such as CCK. As a consequence, the homeostaticsetting is geared for the intake of larger meals because morefood must be consumed before a sufficient satiation signal isgenerated to stop eating. This situation of extra-large mealspersists until body weight (and hence the insulin/leptin signal)returns to normal. Conversely, after excessive weight gain,the increased insulin/leptin brain signal results in increasedsensitivity to satiation signals, and smaller meals are consumeduntil the excess weight is lost. A major dilemma facing cliniciansand others involved in public health is the slippage in thelatter limb of this homeostatic system that permits excessiveenergy storage, obesity, and the associated diseases of nutritionalexcess; e.g. diabetes, cardiovascular disease, and some cancers.
By definition, satiation factors, when administered to humansor animals at the start of a meal, result in a smaller-than-normalmeal being consumed. Exogenously administered satiation factors,or endogenous secretion of these compounds, activates specificreceptors that cause premature cessation of eating. There areseveral excellent reviews of satiation signals such that onlythe salient points need to be reviewed here (7, 8, 9, 12, 13,14). It is generally accepted that for an endogenous compoundto be considered a satiation signal, it is secreted in responseto food ingestion, acts within the time frame of a single meal,reduces meal size without creating malaise or incapacitation,and is effective at physiological doses, and removing or antagonizingits endogenous activity increases meal size (7, 15).
The best-established satiation signals are secreted from specializedenteroendocrine cells in the wall of the GI tract in responseto the digestion and absorption of meals. In the classic modelof satiation, local sensory nerves express receptors for thesegut peptides as they are secreted such that the brain is immediatelyinformed about the nutritional content of the meal by monitoringthe level of hormones secreted to cope with it. As a complexmeal is consumed, the mix of macronutrients (carbohydrates,fats, and proteins) stimulates a proportional blend of satiationpeptides, and an overall message indicating meal content isintegrated in the hindbrain where it activates appropriate responses,including ultimately cessation of the meal. In humans, thisis associated with a sensation of fullness. Although not allintestinal hormones double as satiation signals, they all presumablycontribute to the assimilation of nutrients; i.e. by stimulatingthe secretion of appropriate enzymes, water, and other compoundsinto the lumen of the gut and regulating GI motility. Table1 provides a list of GI and other meal-related hormones/peptidesthat are generally considered to be satiation signals.
CCK was the compound first identified to fit the criteria fora satiation factor, so that much is known about its actions.Consequently, CCK has become the model for the larger classof satiation factors. When food containing fat or protein isconsumed and enters the duodenum, CCK is secreted from I cells.CCK enters the blood and has hormonal influences on gut motility,contraction of the gallbladder, pancreatic enzyme secretion,gastric emptying, and gastric acid secretion (16, 17, 18, 19).However, CCK also diffuses locally to provide a paracrine stimulusto CCK-1 receptors on nearby branches of vagal sensory nerves(20, 21, 22, 23). Through this mechanism a message, generallythat ingested fat/protein is being processed and will soon beabsorbed, is conveyed to the hindbrain and relayed to the hypothalamuswhere it is integrated into the composite information on energyhomeostasis (20, 24, 25, 26, 27, 28) (Fig. 2).
FIG. 2. Satiation signals arising in the GI system converge on the dorsal hindbrain (D) where they are integrated with taste and other inputs. The dorsal hindbrain makes direct connections with the ventral hindbrain (V) where neural circuits direct the autonomic nervous system to influence blood glucose and where the motor control over eating behavior is located. The dorsal hindbrain also conveys information on satiation and other factors anteriorly to the hypothalamus and other brain areas. These areas in turn integrate satiation and adiposity signals as well as available nutrients with experience, the social situation and stressors, and with time of day and other factors. The integrated information is then conveyed posteriorly back to the ventral hindbrain as well as to the pituitary to influence all aspects of energy homeostasis. Animals lacking neural connections between the hindbrain and the hypothalamus reduce the intake of individual bouts of eating when the stomach is distended or they are administered CCK. However, those animals cannot regulate their body weight and are not sensitive to past experience, time of day, or social factors (243 ).
The decrease of meal size elicited by exogenous CCK is dose-dependent,with higher doses causing greater reductions of meal size. However,CCK does not prevent meals from occurring; rather, it decreasesthe size of the meal once it has begun, reducing hunger andincreasing fullness without concomitant sensations of illnessor malaise. When a CCK-1 receptor antagonist is administeredbefore the presentation of food to animals or humans, larger-than-normalmeals are consumed (29, 30, 31), providing compelling evidencethat endogenous CCK normally acts to suppress intake duringmeals. However, the effect of exogenous CCK is short-lived;the meal-reducing signal does not carry over to a second meal.Moreover, the effect of repeated or chronic administration ofCCK (32, 33) has no effect on body weight because the short-termregulation of meal size is overridden by overall energy balance.That is, in the context of lower adiposity, leptin and insulinsignals to the brain are reduced and satiation factors likeCCK 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 effectsof CCK-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 suppressionof ghrelin (37). This latter finding suggests that beyond directlyinhibiting food intake, CCK acts as a proximal mediator of thebroader satiation process. Two minor single nucleotide polymorphismsin the CCK-1 receptor gene promoter have been associated withincreased body fatness, but the mechanism of this associationhas not been explained (38).
Glucagon-like peptide-1
Glucagon-like peptide-1 (GLP-1) is derived from proglucagonin intestinal L cells that are most prevalent in the ileum andcolon (39). GLP-1 secretion is elicited by nutrients, but themechanism whereby the distal L cells are stimulated early withinmeals may require neurohumoral signals initiated in the proximalregions of the small intestine (40). GLP-1 has a broad rangeof actions on glucose metabolism (41), most prominently stimulationof 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 inhibitoryfeedback mechanism that regulates transit of nutrients throughthe course of the GI tract (42, 43). It has generally been assumedthat GLP-1 mediates these various actions through an endocrinemechanism, by binding directly to key target tissues like pancreaticislet cells. However, this mechanism has recently been calledinto question, in large part because GLP-1 is rapidly metabolizedin the circulation by the protease dipeptidyl peptidase IV (DPP-IV)(44). Indeed, the half-life of GLP-1 in human plasma is only1–2 min, and the product of DPP-IV action, a truncatedGLP-1, is inactive with regard to glucose metabolism (45). Becausethe GLP-1 receptor (GLP-1r) is expressed by peripheral and CNSneurons as well as by cells in the pancreatic islets and theGI tract, recent attention has focused on neural mechanismsof GLP-1 action (46, 47, 48).
GLP-1 administration reduces food intake in animals and humans(49, 50, 51, 52, 53, 54), and these anorectic actions are thoughtto be mediated through both peripheral and central mechanisms.A population of neurons that synthesize GLP-1 is located inthe brain stem and projects to hypothalamic and brain stem areasimportant in the control of energy homeostasis (55, 56). Centrallyadministered GLP-1 reduces food intake through at least twomechanisms. GLP-1r in the hypothalamus appear to reduce intakeby acting on caloric homeostatic circuits (57, 58, 59, 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 thehalf-life of active GLP-1 is less than 2 min, any direct effectsare likely transient, and the reduction of food intake may resultfrom inhibitory effects of GLP-1 on GI transit and reduced gastricemptying (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 effectiveat reducing blood glucose in persons with type 2 diabetes andalso cause weight loss (70). In addition, inhibitors of DPP-IV,which elevate endogenous GLP-1 levels, are also effective atimproving glycemic 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 administrationof GLP-1r agonists work around the homeostatic systems controllingbody weight. Indeed, nausea, a hallmark feature of nonhomeostaticanorexia, is very common with GLP-1r agonist treatment (73),although this response wanes with continued treatment and isnot present in all persons who lose weight. Another possibleexplanation for why patients treated with indictable GLP-1ragonists lose weight is that repeated pharmacological dosesof a satiation signal can overcome homeostatic restraints. Consistentwith this hypothesis is the failure of DPP-IV inhibitor treatment,which has a smaller effect to raise circulating concentrationsof GLP-1r agonist activity than do injectable GLP-1 mimeticsto cause weight loss. Although it is not yet clear how GLP-1ragonists cause weight loss, the fact that they do challengesthe current model of the interaction of satiation factors withoverall energy homeostasis.
Glicentin, GLP-2, oxyntomodulin, and glucagon
Other peptides derived from the processing of proglucagon includeglicentin, GLP-2, and oxyntomodulin, as well as glucagon itself(39). Glicentin inhibits gastric acid secretion (74), but atleast 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 peripherally(75, 76). Although a unique receptor for oxyntomodulin has yetto be identified, oxyntomodulin may exert its anorectic effectthrough the GLP-1r because subthreshold doses of the GLP-1rantagonist, exendin (9–39), block both GLP-1 and oxyntomodulin-inducedreductions in food intake (75). Oxyntomodulin is thought tocross the blood-brain barrier and stimulate neurons in the arcuatenucleus (ARC) that express GLP-1r and control energy homeostasis(77, 78). Long-term treatment with oxyntomodulin causes a persistentdecrease in food intake and attenuated weight gain in rats (79).Interestingly, weight loss in animals given oxyntomodulin chronicallyis greater than what would be anticipated from reduced caloricintake (78), suggesting additional effects on energy expenditure.
Short-term treatment with iv oxyntomodulin decreases hunger,reduces consumption of an ad libitum meal, and has an anorecticaction that persists for 12 h after cessation of treatment inlean humans (80). Moreover, in obese subjects randomized toinjections of oxyntomodulin or placebo before each meal for4 wk, there was a significant loss of weight associated withactive treatment. Oxyntomodulin caused an approximately 0.5kg/wk reduction in body weight and was generally well tolerated.These findings suggest that at least two proglucagon productsmay have a role in the regulation of food intake. Distinguishingbetween the effects of GLP-1 and oxyntomodulin, in particularthe relative in vivo actions on the GLP-1r, is an importantnext step in applying these compounds to clinical medicine.
GLP-2 acts through a specific GLP-2 receptor to stimulate intestinalmucosal growth and has become the focus of research on short-bowelsyndrome (81, 82). GLP-2 and GLP-1 have nearly 50% sequencehomology and are secreted in parallel from perfused ileal preparations(83). Intracranial administration of GLP-2 reduces food intakein rats, and the effect can be blocked with a specific GLP-1rantagonist (84). More recent studies in humans found no effectof iv GLP-2 on food intake (85).
Glucagon is the most widely studied hormone cleaved from preproglucagon(39). It is secreted from both pancreatic A cells and probablyalso in small amounts from the distal intestine. The best knownaction of glucagon is to increase hepatic glucose productionby stimulating glycogenolysis and gluconeogenesis. Glucagonalso reduces meal size when administered systemically (86, 87),but not centrally (88), the signal being detected in the liverand relayed to the brain (89). A role for glucagon in the normalcontrol of meal size was demonstrated by the observation thatblocking endogenous glucagon action in rats increases food intake(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 alsoincludes pancreatic polypeptide and neuropeptide-Y (NPY). Likeproglucagon-derived peptides, PYY is synthesized and secretedby L cells in the distal ileum and colon (92). PYY is secretedas PYY (1–36) and is metabolized to PYY (3–36) byDPP-IV (93, 94). Receptors that mediate the effects of PYY,including reduction of food intake, belong to the NPY receptorfamily and include Y1, Y2, Y4, and Y5 (95). However, PYY (3–36)is a highly selective agonist activity for the Y2 receptor,and it also reduces food intake in humans and animals (96, 97).Like GLP-1, PYY has been implicated in GI motility and is considereda major component of the ileal brake (98, 99). Secretion ofPYY is stimulated by food intake (100) and also by the presenceof nutrients within the ileum itself (101); lipid seems to bea particularly effective stimulus. Similar to the case withGLP-1, it is not clear whether PYY release requires direct nutrientcontact with L cells, or if neurohumoral signals originatingfrom the more proximal GI tract mediate the response. Thereis evidence that PYY influences food intake through its interactionwith Y2 receptors in the ARC because it freely crosses the blood-brainbarrier (102) and because systemic PYY (3–36) is ineffectivein reducing food intake in the Y2-deficient mouse (103).
Studies in humans have demonstrated that PYY signaling reducesfood intake and that abnormalities in this system are presentin obese subjects. PYY secretion is proportional to the caloriccontent of meals, with larger meals eliciting a significantlylarger response (104, 105). Fasting and postprandial levelsof PYY are lower in obese adults compared with lean controls(105, 106). The attenuated rise in PYY after eating has alsobeen observed in obese adolescents (107). Infusion of PYY (3–36)into lean and obese humans reduced food consumption measuredduring test meals (104, 105, 106), although there remains somequestion as to whether this effect of PYY (3–36) is pharmacologicalor occurs at circulating levels seen after eating. Obese subjectsdid not differ in their sensitivity to PYY, and there was nodifference in the relative PYY (1–36) and PYY (3–36)levels after exogenous administration. Taken together, thesefindings suggest that abnormal PYY production, rather than anorecticaction of metabolism, could contribute to obesity.
Interestingly, there is evidence that genetic variations inthe PYY and Y2 sequences are associated with body weight. Acommon gene polymorphism in the Y2 receptor has been associatedwith a reduced likelihood of obesity in a cohort study of menwith a broad range of BMI (108). Additionally, in a survey oflean and very obese men, a polymorphism in the PYY allele wasfound to segregate with increased body weight; this geneticvariant of PYY was also found to have reduced binding to itsreceptor and an attenuated anorectic effect in mice (109). Intotal, the data collected in human studies support a role forPYY in the regulation of food intake and build the strongestcase for any of the satiation factors in the pathogenesis ofobesity.
Apolipoprotein A-IV
Apolipoprotein A-IV (apo A-IV) is synthesized by intestinalmucosal cells during the packaging of digested lipids into chylomicronsthat subsequently enter the blood via the lymphatic system (110).Apo A-IV is also synthesized in the ARC (111). Systemic or centraladministration of apo A-IV reduces food intake and body weightof rats (112), and administration of apo A-IV antibodies increasesfood intake (113). Apo A-IV appears to work by interacting withthe CCK signal (114). Because both intestinal and hypothalamicapo A-IV are regulated by absorption of lipid but not carbohydrate(115), this peptide may be an important link between short-and long-term regulators of body fat (see review by Tso andLiu in Ref. 116).
Enterostatin
A second digestion-related peptide, enterostatin, is also closelytied to intestinal processing of lipid. The exocrine pancreassecretes lipase and colipase to aid in the digestion of fat,and enterostatin, a pentapeptide, is cleaved from colipase inthe intestinal lumen and enters the circulation. Administrationof exogenous enterostatin either systemically (117, 118) ordirectly into the brain (119) reduces food intake, and, whenrats are given a choice of foods, the reduction is specificfor fats; that is, enterostatin does not decrease the intakeof carbohydrate or protein (120). Therefore, two peptides thatare secreted from the gut during the digestion and absorptionof lipids, apo A-IV and enterostatin, act as signals that decreasefood intake, and at least one of them selectively reduces theintake of fat. Macronutrient specificity has not been assessedwith apo A-IV. There are no data from human studies to confirmthe findings with apo A-IV and enterostatin on food intake.
Bombesin-family peptides
Members of the bombesin family of peptides including bombesinitself (an amphibian peptide) and its mammalian analogs, gastrin-releasingpeptide (GRP) and neuromedin B (NMB), reduce food intake whenadministered systemically in humans and animals or into theCNS of animals (121, 122, 123). Consistent with the possibilitythat these peptides act endogenously to reduce food intake,mice deficient for the GRP receptor eat significantly largermeals and develop late-onset obesity (124). Whereas most satiationfactors act by reducing the size of an ongoing meal (4), bombesinpeptides are an interesting exception in that when they areadministered between meals, they increase the amount of timeuntil the subsequent meal begins; i.e. they increase satietyas well as satiation (125, 126).
Both bombesin and GRP reduce food intake when infused into humansubjects (127, 128). Antagonism of endogenous bombesin receptorshas demonstrable effects on gastric, intestinal, and gallbladderfunction but has not been studied with regard to food intake(129, 130). Therefore the case for GRP as a physiological mediatorof satiation in humans is not as strong as for CCK.
Amylin
Amylin (also called islet amyloid polypeptide) is a peptidehormone secreted by pancreatic B cells in tandem with insulinsecretion, which inhibits gastric emptying and gastric acidsecretion, lowers glucagon concentrations, and reduces foodintake (131). Amylin causes a dose-dependent reduction of mealsize when administered systemically or directly into the brain(132, 133, 134, 135, 136), and antagonism of amylin action inthe CNS causes increased food intake and body weight (137).Consistent with this, targeted deletion of the amylin gene causesincreased body weight in mice.
Amylin signals through the calcitonin receptor when it has beenmodified 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 anorecticaction of amylin shares features with both satiation signals(phasic, meal-induced secretion) and adiposity signals (chronicinterruption of action in rodents causes increased body fatness).Amylin seems to interact with both types of regulation in thatthe ability of amylin to reduce meal size is augmented whenbrain insulin action is elevated (141) and the effects of CCKand bombesin are muted in the absence of amylin signaling (142).
Amylin has been developed as a therapeutic, with the syntheticanalog pramlintide now available for the treatment of type 1and type 2 diabetes and clinical trials under way to determinethe efficacy in treating obesity. In diabetic patients treatedwith pramlintide for 1 yr, weight loss averaged approximately2 kg relative to placebo-treated controls (143, 144). Similarto treatment with the GLP-1r agonist exendin-4, pramlintidepresents supraphysiological levels of amylin-like activity topatients, and the primary side effect is nausea. Nonetheless,the clinical experience with pramlintide supports the idea thatchronic activity of a satiating compound can cause weight loss.
Ghrelin
Ghrelin, a product of specific endocrine cells in the stomachand 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 identifiedas the endogenous ligand for the GH secretagogue receptor. Fastingincreases plasma ghrelin (146), and exogenous ghrelin increasesfood intake when administered peripherally or centrally (147,148, 149). Ghrelin has also been linked to the anticipatoryaspects of meal ingestion because levels peak shortly beforescheduled meals in humans and rats (150) and fall shortly aftermeals end. Moreover, elevated ghrelin has been linked to thehyperphagia and obesity of individuals with the Prader-Willisyndrome (151). Ghrelin is also unique among the GI signalsin that its message appears to be conveyed directly to receptorsin the hypothalamus (152, 153, 154, 155), although, as is thecase for CCK, GLP-1, and other GI signals, there are ghrelinreceptors on vagal sensory nerves (156) but they do not appearto signal satiation (157).
Satiation signals: summary of general principles
Satiation appears to be a complex phenomenon, mediated by anumber of GI peptides. Although it is clear that the differentsatiation factors respond to specific nutrient stimuli (e.g.CCK to protein and fat, GLP-1 to carbohydrate and fat, PYY primarilyto fat, and so on), it has not been proven that mixed mealsof differing macronutrient content elicit the release of distinctcocktails of GI hormones. However, given the wide range of specificfactors that seem to mediate satiation, it is logical to presumethat this 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 regulationof eating 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 andinfluence satiation are also synthesized in the brain. Thisincludes CCK, GLP-1, GLP-2, oxyntomodulin, apo A-IV, GRP, NMB,PYY, and ghrelin. Exceptions are the pancreatic hormones thatinfluence energy homeostasis (i.e. insulin, glucagon, and amylin)and the 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 intakeare also synthesized locally in the brain raises the questionof whether and how the same signals secreted from differentplaces in the body interact. A simple generalization is that,if a peptide reduces (or increases) food intake when administeredsystemically, it probably has the same action when administeredcentrally. With regard to changes of food intake, this is trueof CCK, GLP-1, apo A-IV, GRP, NMB, PYY, and ghrelin. Interestingly,it is also generally true that peptide signals that are notsynthesized in the brain nonetheless have the same effect onfood intake when administered directly into the brain. Thisis 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 intestinesdecrease food intake, only one known factor, ghrelin, increasesit. One possibility relates to the phenomenon of satiation itselfand the benefits of meal termination. Meals end long beforeany physical limit of the stomach is reached. This is easilydemonstrated when food is diluted with noncaloric bulk and animalsincrease the volume of food consumed to attain their normalcaloric load (158, 159). It has therefore been argued that aprimary function of satiation signals is to prevent the consumptionof 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 challengesto biochemical homeostasis. A corollary to this role for satiationsignals is that adequate food intake does not require much specificstimulation, 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 decreased dueto homeostatic regulation of body energy stores. Evidence forthis was demonstrated for the satiating action of CCK in geneticallyobese Zucker rats (161, 162), but not for rats rendered obeseby lesions of the ventromedial hypothalamus (163). Furthermore,rats genetically prone to becoming obese when fed a high-fatdiet (diet-induced obesity rats) are actually more sensitiveto the satiating action of CCK both before and after becomingobese (164). Some strains of genetically obese mice are comparablyas sensitive as lean controls (165), and CCK works well in obesehumans when administered iv (166). Hence, there is no generalprinciple with regard to sensitivity in obesity, at least withregard to CCK. There is evidence that the satiating action ofGLP-1 is leptin-dependent (167). All of these observations weremade with animals having relatively free access to their dietsso that they could vary their meal patterns in the service ofmaintaining body fat; i.e. when individuals are constrainedto eating only small meals, they compensate by eating more often,thereby maintaining daily caloric intake and body weight. Thishas been observed when CCK is administered before every mealin experimental animals; animals receiving this treatment eatsmaller and more frequent meals while keeping body weight constant(33, 168). In contrast, if animals are constrained to eatingonly three meals a day and receive a satiating peptide at eachmealtime, they cannot compensate and consequently lose weight(169). The advent of long-acting formulations of GLP-1 and amylin,peptides that seem to have a role in satiation (170, 171), hasresulted in weight loss (172, 173). However, at present it isnot clear that the chronic effects of GLP-1 and amylin receptoragonists are entirely due to continued hypophagia as opposedto other, nonbehavioral actions of the compounds. Understandinghow a chronic pharmacological stimulus to the satiation systemlowers body weight is important for refining the models fornormal energy homeostasis.
Insulin from the pancreatic B cells and leptin from white adipocytes(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 influenceenergy homeostasis. Hence, neurons sensitive to insulin and/orleptin receive a signal directly proportional to the amountof fat in the body. Consistent with this, if exogenous insulinor leptin is added locally into the brain, the individual respondsas if excess fat exists in the body; i.e. food intake is reducedand body weight is lost. Analogously, if either the leptin orthe insulin signal is reduced locally in the brain, the individualresponds as if insufficient fat is present in the body, morefood is eaten, and the individual gains weight. There are manyreviews of these phenomena (1, 2, 87, 176, 177, 178).
An important distinction is that whereas satiation signals primarilyinfluence how many calories are eaten during individual meals,adiposity signals are more directly related to how much fatthe body carries and maintains. Developing novel compounds thatinteract directly with the normal detection of and responseto adiposity signals would therefore seem a more promising therapeuticapproach for obesity. A key question therefore is whether agonistsfor the leptin and/or insulin receptor would be viable targetsfor the pharmaceutical industry. One obstacle is that to beeffective, any compound would have to gain access to key receptorsin the brain, yet any such compound would most likely have tobe administered systemically. Administering insulin systemicallyelicits hypoglycemia and other side effects, and hypoglycemiaper se increases food intake (179, 180, 181), thus working againstthe therapeutic intent. Systemically administered insulin doesresult in reduced food intake when plasma glucose is preventedfrom decreasing in animal models (182, 183), but this wouldbe difficult to achieve therapeutically. Alternatively, thereare reports that some formulations of nasally administered insulinelicit reduced food intake and body weight in humans withoutaltering plasma glucose (184, 185).
Leptin does not have the same counterproductive systemic effectsas insulin, and in fact improves insulin sensitivity and circulatinglipoprotein concentrations in subjects with metabolic abnormalitiesassociated with anti-HIV treatment (186). Moreover, chronicleptin treatment of patients with generalized lipodystrophycauses significant improvements of insulin resistance, hypertriglyceridemia,hepatic steatosis, and glucose metabolism (187), responses foundacross the spectrum of lipodystrophies. However, the resultsof clinical trials using leptin in healthy obese subjects havebeen variable, with significant weight loss, but not of a remarkablemagnitude, and some bothersome side effects related to peptideadministration.
Insulin and leptin resistance characterize the obese state,meaning that more of each hormone is required to achieve a particularphysiological effect than occurs in lean individuals. Individualswith diabetes cannot achieve a maximum insulin response becauseof defects in insulin secretion and insulin action. The insulinand leptin resistance that characterizes peripheral tissuesin obesity is also manifested in the brain. For one thing, thetransport of both hormones from the blood to the brain is compromisedin obesity such that less signal reaches critical neurons (188,189, 190), and the ability of those neurons to respond is alsocompromised. When insulin is administered locally into the brainnear the hypothalamus, both genetically obese (191) and dietaryobese individuals (192) have a reduced or absent reduction offood intake, and this is the case for leptin as well (193).Hence, an inability on the part of the brain to respond to signalsindicating that there is excess fat in the body may be a contributingand/or confounding factor in obesity. An insulin mimetic thatinteracts with the insulin receptor and is efficacious whengiven 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.
Although receptors for insulin and leptin are found in severaldiscrete areas throughout the brain, many that are especiallyimportant for controlling energy homeostasis are localized inthe ARC of the hypothalamus (Fig. 1). The ARC is ideally suitedas a receptor site for body adiposity as well as for integrationof diverse hormonal and neural signals because there is evidencethat blood-borne molecules have relatively greater access toreceptors there than to other brain areas, and this is thoughtto be due in part to a relatively leaky blood-brain barrierin the ARC (196, 197). Two categories of ARC neurons are particularlyimportant. One synthesizes the prepropeptide, proopiomelanocortin(POMC), and in the ARC POMC is cleaved to -melanocyte-stimulatinghormone (MSH) as a neurotransmitter. MSH acts at melanocortin3 and melanocortin 4 receptors (MC3R and MC4R) on neurons inother hypothalamic areas and elsewhere in the brain to reducefood intake, and synthetic agonists for MC3R/MC4R are availablethat cause hypophagia and weight loss in experimental animals(see reviews in Refs. 1, 2, 196 and 198, 199, 200, 201, 202).The catabolic action of both leptin and insulin relies uponMSH signaling because administration of antagonists to MC3R/MC4Rblocks each of their actions in the brain (203, 204).
The second group of ARC neurons synthesizes and secretes twoneuropeptides important in energy homeostasis, and their axonsproject to many of the same brain areas as POMC neurons. Agouti-relatedpeptide (AgRP) is an antagonist at MC3R and MC4R (199) suchthat one action of these neurons is to counter the activityof POMC neurons. NPY acts at Y receptors to stimulate food intake(205, 206, 207). When either AgRP or NPY is administered chronicallyinto the brain, body weight increases (202, 208, 209, 210, 211).In fact, when a single dose of AgRP is administered into thebrain near the ARC, food intake is increased for 1 wk or more(212, 213). Insulin and leptin each have a net effect to suppressthe activity of NPY/AgRP neurons in the ARC.
The POMC and NPY/AgRP neurons in the ARC share many importantfeatures. Each is the origin of tracts projecting to other hypothalamicand brain areas, the two tracts often occurring in parallel.The POMC-originating tract has an overall catabolic effect suchthat when it is more active food intake is reduced, energy expenditureis increased, and if prolonged, body fat is lost. Conversely,the NPY/AgRP-originating tract is anabolic, with heightenedactivity causing more food to be ingested and body fat to increase.Under normal conditions, both circuits are active such thata change of input that is either stimulatory or inhibitory toeither 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 projectingto behavioral sites as well as autonomic circuits influencinghepatic glucose secretion and pancreatic insulin secretion (214,215, 216).
Another important aspect of the area including the ARC and nearbyhypothalamic nuclei is that receptors for many of the satiationsignals discussed above are expressed there; i.e. circulatingghrelin 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 peptidesare 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 hindbrainsatiation area and elsewhere in the brain project to the regionof the ARC (25, 27, 217). Finally, ARC neurons are also sensitiveto 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, 223, 224).It is directly sensitive to hormones whose secretion is proportionalto body fat (insulin and leptin); it receives information onongoing meals either directly or indirectly; and it is sensitiveto local levels of nutrients. Importantly, numerous neuronalcircuits interconnect the ARC and nearby hypothalamic areaswith the nucleus of the solitary tract, enabling the hypothalamichomeostatic network to be constantly aware of ongoing GI activitywhile at the same time influencing brain stem autonomic areasprojecting to the GI tract, liver, pancreas, and other tissues(25, 27, 225, 226, 227). The ARC can therefore be consideredas a key afferent as well as efferent area for the regulationof energy homeostasis.
Although ARC neurons project throughout the brain, two nearbytarget areas are thought to be especially important. The paraventricularnuclei (PVN) express both MC3R/MC4R and various Y receptors,and PVN neurons in turn synthesize and secrete neuropeptidesthat have a net catabolic action, including CRH and oxytocin.Administration of exogenous CRH (228) or oxytocin (229) intothe brain reduces food intake. Hence, a catabolic circuit existsin which an increase of body fat is associated with increasedinsulin and leptin, increased MSH, and decreased NPY and AgRPactivity, and consequently increased activity of CRH, oxytocin,and other catabolic signals; all of these lead in turn to reducedfood intake and increased energy expenditure.
The lateral hypothalamic area (LHA) has a contrasting profilefrom the PVN (230). It also receives direct inputs from theARC, and it contains neurons that synthesize and secrete anabolicpeptides, including melanin-concentrating hormone and the orexins.Administration of melanin-concentrating hormone (231, 232) ororexin agonists (233) increases food intake and body weightgain. The architecture and functioning of these opposing hypothalamiccircuits therefore enables rapid and fine-tuned control overenergy homeostasis because the brain can simultaneously turnup one system (e.g. catabolic or anabolic) while turning downthe other.
Total food intake each day is the sum of the intake in individualmeals (including snacks). As discussed above, the time thatmeals are initiated is often under the control of nonhomeostaticinfluences (4, 5, 160, 234). Hence, whatever regulatory controlexists for body weight must be exerted on how much is eatenin individual meals, and meal termination is consequently underthe influence of satiation signals. The efficacy of satiationsignals to terminate a meal varies with the amount of fat inthe body as signaled to the brain by leptin and insulin. Whenan individual has been food restricted (or been on a diet) andloses weight, leptin and insulin secretion both decline, anda reduced adiposity signal reaches the ARC. This in turn lowerssensitivity to satiation signals such as CCK, and the consequenceis that more food is eaten during meals before satiation orfeeling full occurs. Conversely, individuals who have overeatenand gained weight have elevated levels of adiposity signalsand enhanced sensitivity to satiation signals, reducing thetrajectory of weight gain or even promoting weight loss. Whenlow doses of leptin or insulin are infused directly into thebrain near the ARC, they greatly enhance the ability of satiationsignals to reduce food intake [e.g. much less CCK or other satiationsignals is required to terminate a meal (235, 236, 237, 238,239, 240, 241)], and when the adiposity signal in the brainis reduced, satiation signals are less efficacious (242).
The brain receives and integrates diverse information pertinentto the maintenance of energy homeostasis. Adiposity signalssuch as insulin and leptin act in the arcuate nuclei to providea background tone, and this tone in turn determines the sensitivityof the brain to satiation signals influencing how much foodis eaten at any one time. It is important to recognize thatthis "homeostatic" mechanism provides at most a background influence,and that it only subtly influences intake during any given meal.This is because social factors, palatability, habits, the presenceof predators, stress, and many other factors are also alwaysat work, influencing not only when meals occur but how muchfood is consumed as well. Only when extraneous factors are tightlycontrolled 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.
Footnotes
This work was supported by National Institutes of Health AwardsDK 17844 and DK 57900.
Disclosure Summary: S.C.W. received lecture fees from Sanofi-Aventisand from Merck. D.A.D. received lecture fees from Merck, Takeda,and MannKind.
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). The ARC is ideally suited as a receptor site for body adiposity as well as for integration of diverse hormonal and neural signals because there is evidence that blood-borne molecules have relatively greater access to receptors there than to other brain areas, and this is thought to be due in part to a relatively leaky blood-brain barrier in the ARC (196, 197). Two categories of ARC neurons are particularly important. One synthesizes the prepropeptide, proopiomelanocortin (POMC), and in the ARC POMC is cleaved to 
-melanocyte-stimulating hormone (
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Abstract
Introduction
