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Gastrointestinal regulation of food intake




Review series;Gastrointestinal regulation of food intake;David E. Cummings and Joost Overduin;Division of Metabolism, Endocrinology and Nutrition, Department of Medicine, University of Washington;Veterans Affairs Puget Sound Health Care System, Seattle, Washington, USA.;Despite substantial fluctuations in daily food intake, animals maintain a remarkably stable body weight, because;overall caloric ingestion and expenditure are exquisitely matched over long periods of time, through the process of;energy homeostasis. The brain receives hormonal, neural, and metabolic signals pertaining to body-energy status;and, in response to these inputs, coordinates adaptive alterations of energy intake and expenditure. To regulate food;consumption, the brain must modulate appetite, and the core of appetite regulation lies in the gut-brain axis. This;Review summarizes current knowledge regarding the neuroendocrine regulation of food intake by the gastrointestinal system, focusing on gastric distention, intestinal and pancreatic satiation peptides, and the orexigenic gastric;hormone ghrelin. We highlight mechanisms governing nutrient sensing and peptide secretion by enteroendocrine;cells, including novel taste-like pathways. The increasingly nuanced understanding of the mechanisms mediating;gut-peptide regulation and action provides promising targets for new strategies to combat obesity and diabetes.;Principles of satiation;Satiation refers to processes that promote meal termination;thereby limiting meal size (1, 2). Satiety refers to postprandial;events that affect the interval to the next meal, thereby regulating meal frequency, which is also influenced by learned habits (3).;Satiation results from a coordinated series of neural and humoral;signals that emanate from the gut in response to mechanical and;chemical properties of ingested food. Although the relevant signals are commonly dubbed satiety signals, this term is usually a;misnomer, because most of them promote termination of ongoing;meals and do not delay subsequent meal initiation or affect intake;if delivered between meals (4).;A primary function of the gut is to achieve efficient nutrient;digestion and absorption, many satiation signals optimize these;processes by influencing gastrointestinal (GI) motility and secretion. Their additional capacity to limit meal size enhances this;control by restricting the rate at which nutrients reach the gut (5).;Meals are typically stopped long before gastric capacity is reached;and when food is diluted with noncaloric bulking agents, the volume ingested increases to maintain constant caloric intake (6).;Therefore, animals can consume much larger meals than they;typically do. A major function of satiation is to prevent overconsumption during individual meals, thereby averting deleterious;consequences from incomplete digestion as well as excessive disturbances in circulating levels of glucose and other nutrients (7).;Satiation signals arise from multiple sites in the GI system;including the stomach, proximal small intestine, distal small intestine, colon, and pancreas, each of which is discussed below (Figure 1 and Table 1). Ingested food evokes satiation by two primary;effects on the GI tract gastric distention and release of peptides;from enteroendocrine cells. The hindbrain is the principal central;site receiving input from short-acting satiation signals, which are;transmitted both neurally (for example, by vagal afferents projecting to the nucleus of the solitary tract) and hormonally (for;Nonstandard abbreviations used: AGRP, agouti-related protein, AP, area postrema;APO AIV, apolipoprotein A-IV, CCK, cholecystokinin, CCK1R, CCK receptor 1, DPP4;dipeptidyl peptidase-4, FA, fatty acid, GI, gastrointestinal, GLP, glucagon-like peptide;GLP1R, GLP1 receptor, MCH, melanin-concentrating hormone, NPY, neuropeptide;Y, PP, pancreatic polypeptide, PYY, peptide YY.;Conflict of interest: The authors have declared that no conflict of interest exists.;Citation for this article: J. Clin. Invest. 117:1323 (2007). doi:10.1172/JCI30227.;example, by gut peptides acting directly on the area postrema [AP];which lies outside the blood-brain barrier). Although the perception of fullness clearly involves higher forebrain centers, conscious;awareness of GI feedback signals is not required for satiation. Even;animals whose hindbrain is surgically disconnected from the forebrain exhibit satiation and respond to GI satiation peptides (8, 9).;Therefore, gut-hindbrain communication is sufficient for satiation, although this normally interacts with higher cognitive centers to regulate feeding.;Pathways relaying short-acting satiation signals from the gut;to the hindbrain also interact at several levels with long-acting;adiposity hormones involved in body-weight regulation, such as;leptin and insulin. Through multifaceted mechanisms, adiposity;hormones function as gain-setters to modulate the sensitivity of;vagal and hindbrain responses to GI satiation signals. Adiposity;hormones thereby regulate short-term food intake to achieve longterm energy balance (10, 11).;Here we provide an overview of the regulation of feeding by;gastric, intestinal, and pancreatic signals. We discuss interactions;among these signals and between short-acting GI factors and;long-acting adiposity hormones. We also highlight new insights;regarding mechanisms by which enteroendocrine cells sense;and respond to nutrients. The increasingly sophisticated understanding of these topics should help guide development of novel;antiobesity therapeutics.;Gastric satiation signals;Densely innervated by sensory vagal and splanchnic nerves (12);the stomach is optimized to monitor ingestion. Long-standing evidence demonstrates that animals overeat with voluminous meals;if food is drained from their stomach as they eat (13). This observation, however, does not specifically implicate the stomach as a;source of satiation signals, because the exodus of ingesta through;a gastric cannula also precludes meal-related signals that would;normally arise from postgastric sites.;Evidence that the stomach itself contributes to satiation derives;from experiments involving cuffs that can reversibly close the pylorus (the exit from the stomach) and prevent passage of food downstream. Studies using this model demonstrate that major gastric;distention alone is sufficient to terminate ingestion, but the amount;of food required for this exceeds that eaten in a typical meal (2, 14).;The Journal of Clinical Investigation Volume 117 Number 1 January 2007;13;review series;Figure 1;Principal sites of synthesis of GI peptides implicated in the regulation of food intake. Depicted are;the main locations of production for each peptide;although many of these molecules are detectable in;smaller quantities at other sites in the GI system. In;addition, most of them are also synthesized within;the brain, including CCK, APO AIV, GLP1, oxyntomodulin, PYY, enterostatin, ghrelin, gastrin-releasing;peptide (GRP), neuromedin B (NMB), and possibly;PP. GI peptides that regulate appetite and do not;seem to be produced within the brain include leptin;insulin, glucagon, and amylin.;However, normal postprandial gastric distention does contribute;to satiation when acting in concert with pregastric and postgastric;stimuli (2, 14). Oral and gastric stimuli happen concurrently during;eating, and up to 40% of a meal empties into the intestine before;meal termination (15). Therefore, pregastric, gastric, and intestinal;satiation signals commence almost simultaneously, and they function in unison, augmenting each others satiating effects (14).;Gastric satiation signals arise primarily from mechanical distention, whereas those from the intestine derive largely from the;chemical effects of food (16). Hence, with the pylorus closed, gastric loads limit ingestion solely on the basis of their volume, rather;than their nutrient content, osmolarity, or pH (17). Although;the stomach can sense nutrients (for example, to regulate gastrin;release) (18), this does not seem to contribute to satiation. The;stomach wall is endowed with discrete neural sensors of tension;(19), stretch (20), and volume (14). Output from these mechanoreceptors is relayed to the brain by vagal and spinal sensory nerves;(14, 21), using a complex array of neurotransmitters and neuromodulators, including glutamate, acetylcholine, nitric oxide, calcitonin-gene-related peptide, substance P, galanin, and cocaine-andamphetamine-related transcript (14).;Bombesin-related peptides (for example, gastrin-releasing peptide;and neuromedin B), which are produced by gastric myenteric neurons, can reduce food intake when delivered pharmacologically;to humans and other animals (2). Because it is not clear, however;whether these peptides are regulated by ingested nutrients, they are;not discussed in this review of meal-related GI signals.;Intestinal satiation;The generally accepted assertion that gastric satiation is volumetric, intestinal satiation is nutritive (16) reflects the importance of;nutrients in mediating intestinal satiation, with a limited role for;distention. Intestinal nutrient infusions reduce food intake in many;species, including humans (14) an effect that commences within;seconds of nutrient infusion, indicating that at least some of the;associated satiation signals emanate from the gut, rather than from;postabsorptive sources (22). These, and other, findings demonstrate;14;that the intestines play a dominant role in satiation. Many intestinal;satiation signals inhibit gastric emptying, and this probably helps;limit ingestion by enhancing gastric mechanoreceptor stimulation.;However, sham feeding experiments show that a delay of gastric emptying is not required for intestinal signals to elicit satiation (14).;Mediators of intestinal satiation include a cadre of gut peptides;that are secreted from enteroendocrine cells in response to ingested food. These messengers diffuse through interstitial fluids to;activate nearby nerve fibers and/or enter the bloodstream to function as hormones (Figure 2). In conjunction with gastric distention, satiation peptides educe the perception of GI fullness, promoting meal termination. Standards for physiologically satiating;peptides were articulated in the publication describing the first;such agent, cholecystokinin (CCK) (2, 4). According to these criteria, a satiation factor should be released during food ingestion;and exogenous administration of it should decrease meal size in a;dose-dependent manner rapidly, transiently, and at physiologic;concentrations, without causing illness.;Upper-intestinal satiation: CCK;CCK is the archetypal intestinal satiation peptide, first described;as such three decades ago (4). It is produced by I cells in the duodenal and jejunal mucosa, as well as in the brain and enteric nervous;system. Intestinal CCK is secreted in response to luminal nutrients;especially lipids and proteins. The CCK prepropeptide is processed;by endoproteolytic cleavage into at least six peptides, ranging from;8 to 83 amino acids in length (23). The multiple bioactive forms;pertinent to feeding share a common carboxy-terminal octapeptide with an O-sulfated tyrosine. The major circulating moieties;are CCK8, CCK22, CCK33, and CCK58, although recent evidence;suggests that CCK58 might be the only relevant endocrine form;in some species (24). CCK peptides interact with two receptors;expressed in the gut and brain. CCK receptor 1 (CCK1R, formerly;known as CCK-A, for alimentary) predominates in the GI system;whereas CCK2R (formerly known as CCK-B, for brain) predominates in the brain. Through endocrine and/or neural mechanisms;CCK regulates many GI functions, including satiation.;The Journal of Clinical Investigation Volume 117 Number 1 January 2007;review series;Table 1;Selected GI and pancreatic peptides that regulate food intake;Peptide;CCK;GLP1;Oxyntomodulin;PYY336;Enterostatin;APO AIV;PP;Amylin;GRP and NMB;Gastric leptin;Ghrelin;Main site of synthesis;Proximal intestinal I cells;Distal-intestinal L cells;Distal-intestinal L cells;Distal-intestinal L cells;Exocrine pancreas;Intestinal epithelial cells;Pancreatic F cells;Pancreatic cells;Gastric myenteric neurons;Gastric chief and P cells;Gastric X/Alike cells;Receptors mediating;feeding effects;Sites of action of peripheral;peptides germane to feeding;Hypothalamus Hindbrain;Vagus nerve;CCK1R;X;X;X;GLP1R;X?;X?;X;GLP1R and other;X;Y2R;X;X;F1-ATPase subunit;X;Unknown;X;X;Y4R, Y5R;X;X;CTRs, RAMPs;X;X;GRPR;X;X;Leptin receptor;?;?;X;Ghrelin receptor;X;X;X;Effect on;food intakeA;CTRs, calcitonin receptors, RAMPs, receptor activitymodifying proteins, GRP, gastrin-releasing peptide, NMB, neuromedin B, GRPR, GRP receptor. X?;indicates that it is unclear whether physiologically relevant quantities of GLP1 from the gut evade DPP4-mediated degradation in blood to activate GLP1;receptors in the brain, although these receptors might interact with CNS GLP1 to regulate food intake.? indicates that it seems very unlikely that gastric;leptin interacts in a physiologically meaningful way with leptin receptors in the hypothalamus or hindbrain, which are important targets of leptin secreted;from adipocytes. AEffect of peripheral peptides on food intake. In some cases, central administration yields opposite results.;When peripherally injected immediately before a meal, CCK;decreases meal size in a dose-dependent manner without affecting water intake or causing illness (4). Exogenous CCK also;triggers a stereotyped sequence of behaviors that rats normally;display upon meal completion, suggesting that it evokes the perception of satiation without internal food stimuli (25). Typifying;a short-acting satiation signal, the anorectic effects of CCK are;very short-lived and undetectable if the peptide is injected more;than 30 minutes before meals.;Satiating effects of CCK have been confirmed in numerous species, including humans, in whom the carboxy-terminal octapeptide;reduces meal size and duration (26). Pharmacologic and genetic;experiments indicate that CCK1R mediates CCK-induced satiation;(27, 28). This receptor is expressed on vagal afferents, and peripheral;CCK administration increases vagal-afferent firing, as well as neuronal;activity in the hindbrain region receiving visceral vagal input (29, 30).;Furthermore, both subdiaphragmatic vagotomy and selective vagal;deafferentation decrease the anorectic effects of peripheral CCK;(3133). These findings identify a critical vagal pathway for CCKinduced satiation. However, CCK1R is also expressed in the hindbrain;and hypothalamus. Lesions of the hindbrain AP attenuate CCKinduced satiation (34), and CCK microinjections into several hypothalamic nuclei decrease food intake (35). These observations suggest;that CCK might relay satiation signals to the brain both directly and;indirectly, and/or that central CCK contributes to satiation.;As is mentioned above, CCK-induced satiation could result in;part from inhibition of gastric emptying, thereby augmenting;gastric mechanoreceptor stimulation. Some vagal-afferent fibers;respond synergistically to gastric distention and CCK (36), and;subthreshold doses of CCK reduce food intake in monkeys if combined with gastric saline preloads (37). Similarly, gastric distention;augments the anorectic effects of CCK8 in humans (38). However, other studies show no differences in the satiating capacity of;CCK8 between rats eating normally and those either sham fed or;fitted with closed pyloric cuffs (33, 39). These and other observations indicate that CCK causes satiation through mechanisms;additional to enhancing gastric distention signals.;The impact of eliminating CCK1R signaling supports a physiologic role for this receptor in satiation. Rats lacking CCK1R show;increased meal size and gradually become obese (27), a phenotype;possibly driven by overexpression of neuropeptide Y (NPY) in the;dorsomedial hypothalamus (40). The obesity is fairly mild, however, and is not present in CCK1R-deficient mice (28), this is consistent with the proposed function of CCK as a short-acting satiation;signal. CCK1R antagonists also increase meal size and food intake;in experimental animals (41, 42), and they increase hunger, meal;size, and caloric intake in humans (43).;Despite the role of CCK in terminating individual meals, its;importance in long-term body-weight regulation and its potential;as an antiobesity target are questionable. Chronic CCK administration in animals, with up to 20 peripheral injections per day, reduces;meal size, but this is offset by increased meal frequency, leaving body;weight unaffected (44). CCK administration decreases food intake;acutely in humans by shortening meals (45), but anorectic effects;dissipate after only 24 hours of continuous infusion (46). Not;surprisingly, trials of CCK1R agonists as antiobesity therapeutics;have been unsuccessful to date. The most important role for CCK;in body-weight regulation might be its synergistic interaction with;long-term adiposity signals, such as leptin (see below) (10, 11).;Lower-intestinal satiation: glucagon-like peptide-1;The ileal brake is a feedback phenomenon whereby ingested food;activates distal-intestinal signals that inhibit proximal GI motility;and gastric emptying (47). It is mediated by neural mechanisms;and several peptides that are also implicated in satiation. These;engage a behavioral brake on eating to complement the ileal brake;restraining the rate of nutrient entry into the bloodstream (5). One;such peptide is glucagon-like peptide-1 (GLP1). It is cleaved from;proglucagon, which is expressed in the gut, pancreas, and brain;(48). Other proglucagon products include glucagon (a counterregulatory hormone), GLP2 (an intestinal growth factor), glicentin;(a gastric acid inhibitor), and oxyntomodulin. Although several of;these peptides are implicated in satiation, evidence is strongest for;GLP1 and oxyntomodulin.;The Journal of Clinical Investigation Volume 117 Number 1 January 2007;15;review series;Figure 2;Topography of enteroendocrine cells and absorptive enterocytes on;a villus within the small-intestinal wall. Enteroendocrine cells sense;nutritive and non-nutritive properties of luminal food and, in response;release satiation peptides from their basolateral aspect. These signals;diffuse through the lamina propria to activate nearby vagal- and spinalafferent fibers from neurons within the nodose and dorsal root ganglia;respectively, as well as myenteric neurons. Satiation peptides can;also enter the bloodstream to act distantly as hormones. Gut-peptide;release is regulated not only by luminal nutrients but also by somatic;signals. The basolateral side of enteroendocrine cells bears receptors that respond to neurotransmitters, growth factors, and cytokines.;Neurotransmitters mediate duodenal-ileal communication to regulate;L cell secretion, and they enable central modulation of gut-peptide;release. Whether vagal- or spinal-afferent nerves are directly activated by ingested nutrients is uncertain. Although vagal- and spinalafferent fibers approach the abluminal aspect of enteroendocrine cells;and enterocytes, they do not form synapse-like contacts with these;epithelial cells, nor do they extend to the intestinal lumen. Some subepithelial nerve fibers might respond to luminal chemicals that diffuse;across the epithelium, such as FAs, but this applies only to short-chain;FAs, which do not efficiently elicit satiation (116). Other vagal-afferent;fibers respond selectively to intestinal carbohydrates or fats. Although;it is theoretically possible that these neurons sense nutrients in the;extracellular space, it is more clearly established that signaling molecules released from enteroendocrine cells mediate macronutrientspecific neural activation.;GLP1 is produced primarily by L cells in the distal small intestine and colon, where it colocalizes with oxyntomodulin and;peptide YY (PYY). Ingested nutrients, especially fats and carbohydrates, stimulate GLP1 secretion by indirect, duodenally activated neurohumoral mechanisms, as well as by direct contact;within the distal intestine (49). The two equipotent bioactive;forms, GLP1736 amide and GLP1737, are rapidly inactivated in;the circulation by dipeptidyl peptidase-4 (DPP4) (50). In addition;to engaging the ileal brake, GLP1 accentuates glucose-dependent;insulin release, inhibits glucagon secretion, and increases pancreatic cell growth (48). Therefore, DPP4-resistant GLP1 congeners are being developed to treat diabetes.;16;GLP1 decreases food intake in several species (51, 52), including humans (53). Peripheral injections elicit satiety among normal-weight (54), obese (55), and diabetic (56) persons. Importantly, patients with diabetes treated with either GLP1 or the GLP1;receptor (GLP1R) agonist exenatide lose weight progressively in;trials lasting up to two years (57, 58). This is especially remarkable;because improved glycemic control achieved with other agents;typically promotes weight gain.;The mechanisms underlying GLP1-induced anorexia are not;fully known but involve vagal and possibly direct central pathways. Anorectic effects are mediated specifically by GLP1R, as;they are absent in GLP1R-deficient mice and are reversed with;selective GLP1R antagonists (59). GLP1R is expressed by the gut;pancreas, brainstem, hypothalamus, and vagal-afferent nerves;(48). The vagus is required for peripheral GLP1-induced anorexia;which is abolished by vagal transection or deafferentation (60, 61).;Whether peripheral GLP1 also functions through central receptors;is questionable. The peptide can cross the blood-brain barrier, but;it seems unlikely that physiologically relevant quantities of endogenous peripheral GLP1 evade peripheral DPP4 degradation and;penetrate the brain. However, GLP1 is produced by brainstem neurons that project to hindbrain and hypothalamic areas germane;to energy homeostasis, possibly regulating appetite. Activation of;hypothalamic GLP1R decreases food intake without causing illness, whereas GLP1R activation in the amygdala elicits malaise;(62). Although pharmacologic use of exenatide can stimulate the;illness pathway, nausea is not the only mechanism reducing food;intake. There is little correlation between the severity of nausea;and the amount of weight lost, and doses of exenatide too low to;cause nausea do promote weight loss.;Although GLP1 administration can reduce food intake, the;physiologic importance of GLP1 in feeding was challenged by the;observation that GLP1R-deficient mice have normal food intake;and body weight (63). Regardless of its physiologic significance;in energy homeostasis, GLP1R overstimulation offers an attractive pharmacologic antiobesity strategy, because it reduces body;weight while independently ameliorating diabetes.;Lower-intestinal satiation: oxyntomodulin;Like GLP1, oxyntomodulin is a proglucagon-derived peptide;secreted from distal-intestinal L cells in proportion to ingested calories. In rodents, exogenous administration decreases food intake;while increasing energy expenditure, and chronic injections reduce;body-weight gain (64, 65). In humans, i.v. infusion acutely lessens;hunger and single-meal food intake (66), and repeated injections;decreased body weight by 0.5 kg/wk more than placebo in a 4-week;trial (67). In this study, oxyntomodulin reduced buffet-meal intake;(without decreasing palatability) by 25% at the beginning of the;trial and by 38% at the end, indicating no tachyphylaxis. Replicating animal results, the regimen also increased activity-related;energy expenditure (68).;Although the mechanisms mediating these effects are enigmatic;GLP1R is probably involved, since oxyntomodulin does not alter;feeding in GLP1R-deficient mice (59), and the GLP1R antagonist;exendin939 blocks oxyntomodulin-induced anorexia (64). Additional pathways are implicated, however, as oxyntomodulin binds;GLP1R 100 times less avidly than GLP1 does, yet they elicit anorexia at equimolar doses (64). The peptides also have different CNS;targets oxyntomodulin activates neurons in the hypothalamus;(65), whereas GLP1 does so in the hindbrain and other autonomic;The Journal of Clinical Investigation Volume 117 Number 1 January 2007;review series;control areas (69). Moreover, intrahypothalamic exendin939 inhibits anorectic effects of oxyntomodulin but not GLP1 (65), and;studies with GLP1R-deficient mice indicate that the two peptides;differentially regulate feeding and energy expenditure (59).;The crystal structure of oxyntomodulin has been solved, and this;advance should facilitate the rational design of oxyntomodulin;peptidomimetics to be tested as oral antiobesity pharmaceuticals.;Lower-intestinal satiation: PYY;The pancreatic polypeptidefold (PP-fold) family includes PYY;NPY, and PP. All are 36amino acid peptides that require carboxyterminal amidation for bioactivity and share the PP-fold structural;motif. They interact with a family of receptors (Y1R, Y2R, Y4R;Y5R, and Y6R) that couple to inhibitory G proteins. NPY is an;orexigenic hypothalamic neuropeptide, PP is discussed below.;PYY is produced mainly by distal-intestinal L cells, most of;which coexpress GLP1. It is secreted postprandially in proportion to caloric load, with a macronutrient potency of lipids being;greater than that of carbohydrates, which is greater than that of;proteins (70). As with GLP1, postprandial secretion is biphasic;initially stimulated by atropine-sensitive neural projections from;the foregut, followed by direct nutrient stimulation in the hindgut;(71). PYY136 is rapidly proteolyzed by DPP4, unlike GLP1, however, the cleaved product, PYY336, is bioactive. Like GLP1, PYY delays;gastric emptying, contributing to the ileal brake (47).;A role for PYY336 in satiation was asserted in a recent set of studies;heralding this peptide as a promising antiobesity therapeutic (72;73). It was reported that peripheral PYY336 administration, at doses;generating physiologic postprandial blood excursions, reduced food;intake and body weight in rats. In humans, i.v. infusion replicating;postprandial PYY336 concentrations lessened hunger and decreased;buffet-meal intake by 36%, without causing nausea, affecting food;palatability, or altering fluid intake. The reduced food intake was;not followed by compensatory hyperphagia. Interestingly, PYY336;levels were reported to be lower in obese than in lean persons, consistent with a role in obesity pathogenesis. Moreover, anorexia;induced by PYY336 was fully intact in obese individuals, in contrast;to obesity-associated resistance to the anorectic adiposity hormones;leptin and insulin. These findings suggested tantalizing therapeutic;potential for PYY336 and related peptidomimetics.;However, reports that PYY336 causes anorexia surprised some;investigators, because central administration of either PYY136 or;PYY336 potently increases food intake (74). To explain this paradox;a mechanistic model was formulated, based on Y receptor subtype;selectivity and accessibility (72). PYY136 activates all Y receptors;and orexigenic effects are predicted from its interactions with Y1R;and Y5R, which are expressed in the hypothalamic paraventricular;nucleus and are thought to mediate NPY-induced feeding. Accordingly, the feeding effects of central PYY are attenuated in both;Y1R-deficient and Y5R-deficient mice (75). PYY336 selectively activates Y2R and Y5R, and icv administration of this peptide might;increase food intake through Y5R. Circulating PYY336, however;was hypothesized to gain access selectively to Y2R in the hypothalamic arcuate nucleus, an area believed by some to be accessible to;blood. In the hypothalamus, Y2R is a presynaptic autoinhibitory;receptor on orexigenic neurons that express both NPY and agoutirelated protein (AGRP), known as NPY/AGRP neurons. Therefore;the model proposes that circulating PYY336 reduces food intake;by inhibiting NPY/AGRP neurons through Y2R, thereby derepressing adjacent anorectic melanocortin-producing cells, which;are inhibited by NPY/AGRP neurons (72). Consistent with this;model, the feeding effects of PYY336 are abolished by pharmacologic or genetic blockade of Y2R (61, 72, 76). Furthermore, PYY336;administration decreases hypothalamic NPY expression in vivo;and it decreases NPY while increasing -melanocyte-stimulating;hormone release from hypothalamic explants. Finally, intra-arcuate injections of PYY336 inhibit food intake, whereas diffuse icv;injections do the opposite (72).;Despite these findings supporting a hypothalamic mechanism of;action of peripherally administered PYY336, Y2R is also expressed;by vagal-afferent terminals (77), and some investigators hypothesize vagal mediation. Supporting this assertion, anorectic effects;and arcuate neuronal activation elicited by peripheral PYY336 were;eliminated by either subdiaphragmatic vagotomy or transection of;hindbrain-hypothalamic pathways (60, 77).;Several laboratories reported difficulties in replicating anorectic effects of peripheral PYY336 administration, despite using;numerous rodent models, experimental protocols, and chemically;validated PYY336 preparations (78). However, several other groups;have confirmed anorectic and weight-reducing properties of this;peptide in rodents (61, 76, 7983) and nonhuman primates (84).;Because stress reduces food intake, potentially masking additional;anorectic effects, differences in the habituation of animals to experimental procedures could explain some of these discrepancies (79);although this does not settle the entire debate. The timing of injections is also important, efficacy being lost at certain times of day.;The original mechanistic model based on hypothalamic-Y2R-mediated NPY inhibition predicts that anorectic effects of PYY336 would;be maximal at times when arcuate NPY is elevated. Indeed, the initial findings were reported from rodents that were fasting or in the;early dark cycle times when NPY is naturally induced (72).;In summary, the anorectic effects of peripheral PYY336 administration in rodents are subtle and vulnerable to vicissitudes of;animal handling, as well as the dose, route, and timing of injections. Although this might call into question the pragmatism;of PYY-based antiobesity therapeutics, anorectic effects of the;peptide seem to be more robust in primates than in rodents, and;the findings in humans have been corroborated (70). Nevertheless;some pharmaceutical-industry support for clinical development;of intranasal PYY336 has abated because of insufficient efficacy.;Fat-specific satiation peptides: enterostatin and;apolipoprotein A-IV;Some GI peptides are specifically stimulated by fat ingestion;and subsequently regulate intake and/or metabolism of lipids.;Enterostatin is a pentapeptide cleaved from procolipase, which is;secreted from the exocrine pancreas in response to ingested fats;to facilitate their digestion. Procolipase is also produced in the;gut and several brain areas pertinent to energy homeostasis (85).;Both peripheral and central enterostatin administration decreases;dietary fat intake in animals, and enterostatin-receptor antagonists do the opposite (86). The mechanisms underlying these;effects seem complex but involve the F1-ATPase subunit as the;putative enterostatin receptor (87), with downstream mediators;including melanocortins and the 5-hydroxytryptamine (serotonin);receptor 1B (88). Unfortunately, enterostatin administration to;humans has thus far shown no effects on food intake, appetite;energy expenditure, or body weight (89).;Apolipoprotein A-IV (APO AIV) is a glycoprotein secreted from;the intestine in response to fat absorption and chylomicron forma-;The Journal of Clinical Investigation Volume 117 Number 1 January 2007;17;review series;Figure 3;Similarities in nutrient-sensing mechanisms used by taste-receptor cells of the tongue and enteroendocrine cells of the intestine (exemplified by;an L cell). Several types of enteroendocrine cell throughout the gut express components of nutrient-sensing and signal-transduction systems;that were previously thought to be selective to taste-bud cells. These include apical G proteincoupled receptors for sweet and bitter chemicals;the unusual G protein isoforms Ggustducin, G3, and G13, phospholipase C2, and the TRPM5 Ca2+-activated Na+/K+ channel. Additional contributions from plasma membrane delayed-rectifying K+ channels and voltage-gated Ca2+ channels that are important for taste sensation in the;tongue have not yet been confirmed in enteroendocrine cells. In both cell types, the final common pathway for activation inc


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