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Physiologic control of food intake by neural and chemical mechanisms
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Physiologic control of food intake by neural and chemical mechanisms PHIJPPANORTON, MEd, RD; GRACE FALCIGLIA, EdD, RD; DANIEL GIST,PhD
IUIRMT:
Physiologic control of eating involves neural and chemical regulators that may have therapeutic applications in weight control. Information on the nature and quantity of ingested and stored nutrients is relayed to the brain via sensory nerve fibers. This information is integrated at specific centers in the brain, then impulses in motor nerve fibers are discharged leading to initiation or termination of eating. Chemical regulators of eating behavior include gastrointestinal peptides released during digestion, absorbed glucose circulating in the plasma, and the hormonal regulators of glucose metabolism (insulin and glucagon). There is, however, considerable interplay between neural and chemical processes in regulation of food intake. Neural mechanisms are evidently mediated by chemical regulators, because neurotransmitters, including serotonin, allow nerve impulses to cross synapses. In addition, some chemical regulators are concentrated at brain centers that are implicated in regulation of eating behavior. Although some gastrointestinal peptides and serotoninergic drugs have been used to treat obesity, the existence of a complex control system with alternate mediators of food intake suggests that a single therapeutic agent is unlikely to be applied universally to suppress overeating. JAm Diet Assoc. 1993; 93:450-454, 457.
any factors have been implicated in the etiology of obesity; cognitive, environmental, and genetic influences have been widely investigated. For some obese patients, however, eating behavior and body weight may be the consequence of a physiologic impairment. Although numerous studies have probed the physiologic factors that influence eating behavior, details of the neural and chemical processes involved in eating and satiety have yet to be integrated into a model that accurately represents the regulation of food intake. An understanding of these endogenous mechanisms is vital if effective therapies are to be developed for the purpose of weight control in patients whose obesity is the result of physiologic imbalance. In this article we review briefly the neural mechanisms and chemical regulators involved in controlling food intake. Then we describe how these two sets of physiologic signals are integrated to initiate or terminate eating. Finally, we address the possibility of using the physiologic effects of chemical regulators for therapeutic purposes. NEURAL MECHANISMS Role of the Brain in Regulation of Eating Behavior The lateral hypothalamus and the ventromedial hypothalamus were assigned the roles of feeding center and satiety center, respectively, on the basis of early lesion experiments in laboratory animals (1). More recently, anatomic studies and electrophysiologic techniques have been used to investigate the roles of regions outside of the hypothalamus in eating behavior. Figure 1 shows some of the regions of the brain implicated in the control of eating. An association has been demonstrated between the lateral hypothalamus and the nigrostriatal tract: destruction of the latter leads to hypophagia and weight loss (2). The paraventricular nucleus of the hypothalamus is connected to a region in the dorsal medullathe nucleus of the tractus solitarius-destruction of which also results in hypophagia and weight loss in rats (3,4). Thus, eating is not influenced solely by the hypothalamus but also by neural mechanisms operating in other regions of the brain. P. Norton (correspondingauthor) was a graduate research assistantin the Department of Health and Nutrition Sciences at the University of Cincinnati, Cincinnati, OH 45221 at the time of the study; she is currently a renal dietitianwith Dialysis Clinic, Inc, Cincinnati, OH 45206. G. Falcigliais an associate professor of nutritionin the Department of Health and Nutrition Sciences and D. Gist is an associateprofessor iia the Department of BiologicalSciences at the Universit/ (?/ Cincinnati.
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Sensory Input to the Brain Via the vagus nerve, the brain receives sensory information about rates of digestion in the gut and metabolism of nutrients in the liver (5). An increase in glucose content of liver cells after a meal changes the frequency of impulses reaching the nucleus of the tractus solitarius in vagal sensory nerve fibers (6). Autoradiographs show nerve tracts ascending from the nucleus and presumably carrying sensory information from the vagus nerve to the hypothalamus and components of the limbic system in the forebrain (3). Nerve tracts projecting from the hypothalamus and limbic system to vagal motor nerve fibers of the autonomic nervous system via the nucleus of the tractus solitarius (5) may be important motor components of eating behavior. Thus, eating is regulated not only by central mechanisms operating in the brain but also by sensory input to the brain from peripheral structures. CHEMICAL REGULATORS Peripheral Chemical Regulators The presence of food in the gut stimulates the release of gastrointestinal peptides such as somatostatin, cholecystokinin, glucagon, and bombesin, all of which produce a dosedependent decrease in meal size (7-9). Plasma levels of insulin are positively correlated with body fat stores (10), which suggests that body weight may be another factor controlling eating behavior. A product of fat catabolism, 3-hydroxybutyrate, crosses the blood-brain barrier at a higher rate in rats resistant to dietary obesity compared with a strain that is susceptible to obesity (11). Infusion of 3-hydroxybutyrate into the rat brain has also been shown to decrease food intake and body weight (12). Products of fat catabolism may, therefore, be involved in regulating food intake and body weight. Neurotransmitters Chemical regulators synthesized in the brain from assimilated nutrients play a part in controlling eating behavior. For example, accelerated entry of tryptophan into the brain after carbohydrate consumption and insulin secretion promotes synthesis of serotonin, a neurotransmitter implicated in suppression of carbohydrate consumption in rats and obese human beings (13,14). Chemical regulators that increase ingestion of specific, highenergy nutrients are present in the brain. Opioids preferentially stimulate the ingestion of fatty foods (15). Norepinephrine, in contrast, increases preference for sweet and nonsweet carbohydrates in rats (16). Other central feeding-stimulatory chemicals involved in mediating intake of high-energy nutrients include neuropeptide Y (17) and galanin (18). INTEGRATION OF NEURAL MECHANISMS AND CHEMICAL REGULATORS The preceding discussion suggests that mechanisms regulating food intake are activated by a series of neural and chemical signals. The Table summarizes the signals that mediate hunger and satiety These signals, which simultaneously indicate the quantity of ingested food in the gut and the body's requirements for energy, must be integrated to initiate or terminate feeding. Thus, control centers in the brain may direct eating behavior on the basis of information received in the form of nerve impulses and chemical stimuli arising in peripheral tissues. Interactions between neural and chemical signals originating in the brain and peripheral structures are shown in Figure 2. Control of food intake as a result of integration of neural and chemical signals will be the focus of the remainder of this article.
FIG 1. Regions of the brain implicated in regulationof food intake and neuralconnections between them.
Table Principal neural and chemical stimulators of hunger and satiety Hunger Neural Lateral hypothalamus Limbic system Nigrostriatal tract Nucleus of the tractus solitarius Paraventricular nucleus Chemical Dopamine Galanin Insulin (plasma) Neuropeptide Y Norepinephrine Opioids
Satiety Nucleus of the tractus solitarius Paraventricular nucleus Ventromedial hypothalamus
Bombesin Cholecystokinin Insulin (brain) Glucagon Hepatic glucose concentration 3-Hydroxybutyrate Prostaglandins Serotonin Somatostatin
Gastrointestinal Peptides The presence of food in the gut stimulates release of gastrointestinal peptides. These peptides can either enter the circulatory system and ultimately interact with specific centers in the brain or elicit an effect at one or more peripheral sites; satiety signals are relayed via sensory nerve fibers to the brain. Somatostatin is a peripheral mediator of satiety because meal size is decreased by infusion of the peptide into the peritoneal cavity but not by direct administration to the brains of laboratory animals (7). The peripheral action of somatostatin is likely to extend to human beings because intravenous infusion of postprandial concentrations of this peptide inhibit secretion of pancreatic digestive juices in human subjects (19) and presumably decrease the rate of digestion. JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION / 451
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Results of animal studies imply that the satiating effect of cholecystokinin and glucagon is mediated peripherally because food intake is diminished only when vagal sensory fibers are intact (8,20). If these peptides acted directly on the brain, food intake would also decrease in animals subjected to neural disconnection of the brain and gut. Bombesin, like cholecystokinin, decreases meal size in rats only when vagal sensory fibers are intact. However, bombesin also decreases the frequency of eating, and this effect is observed regardless of the integrity of the vagal sensory fibers (9). Bombesin may, therefore, elicit satiety both peripherally and by direct action on the brain. Further evidence of this effect is provided by the decrease in food intake brought about by infusion of bombesin into the lateral hypothalamus, paraventricular nucleus, and nucleus of the tractus solitarius (21,22). Bombesin stimulates release of cholecystokinin in animals and human beings (23,24), and the satiating effect of cholecystokinin in rats is increased by glucagon (25). These results suggest that gastrointestinal peptides may act synergistically to regulate eating behavior, and cholecystokinin, bombesin, and glucagon have indeed been shown to interact in this way to reduce meal size in rats (26). Infusions of bombesin and cholecystokinin have been demonstrated to decrease eating in human beings (27,28), which raises the possibility that gastrointestinal peptides may have therapeutic applications in weight control. Inhibition of food intake by these agents is accompanied, however, by mild abdominal distress. In addition, the issues of long-term safety and efficacy in weight management remain to be addressed. Furthermore, animal experiments have demonstrated that the gastrointestinal peptides signal satiety via different vagal sensory pathways (29-31), suggesting that separate peripheral satiety signals generated by different peptides are integrated in the brain. If this is the case, an opportunity exists for stimuli generated by other central and peripheral satiety mechanisms to interact with and either reinforce or override the signals generated by gastrointestinal peptides. 452 / APRIL 1993 VOLUME 93 NUMBER 4
Hepatic Glucose Metabolism Eating behavior may be modified by autonomic responses in peripheral structures, including the gut and liver. The liver is the immediate destination for end products of digestion absorbed into the hepatic portal system and a storage depot for carbohydrates. Therefore, the liver has the potential to influence ingestive behavior in response to glucose intake and storage. Uptake of glucose by the liver after a meal suppresses the vagal sensory system and decreases the activity of glucosesensitive neurons in the lateral hypothalamus (32). The ventromedial hypothalamus also contains neurons that are sensitive to hepatic glucose concentration, and glucose ingestion increases electrical activity in this region, which leads to satiety (33). Thus, an increase in the amount of glucose absorbed from the gut appears to activate neural mechanisms that may be involved in meal termination. The same neural areas are also implicated in the release of chemical regulators of glucose metabolism. When food is ingested, increases in plasma concentrations of glucagon and insulin precede glucose absorption (34). Electrical stimulation of the ventromedial hypothalamus and lateral hypothalamus also elicits glucagon and insulin secretion, so output of these chemical regulators by the pancreas appears to be a reflex response mediated by hypothalamic nuclei. Adipose Tissue Mass Studies with fasting human beings have shown a positive correlation between insulin levels in plasma and the size of body fat stores (10), and insulin, acting as an index of adiposity, might be expected to play a part in regulating food intake. However, many physiologic processes, including food intake, affect plasma insulin levels. A physiologic increase in insulin in plasma is followed, after an initial lag, by significant elevation of insulin in the cerebrospinal fluid (35). Because cerebrospinal fluid is believed to be formed largely from interstitial fluid in the brain, the appear-
ance of insulin in cerebrospinal fluid must be preceded by entry of insulin from the plasma into the brain. Autoradiographs have demonstrated concentrations of insulin receptors in specific hypothalamic regions associated with food intake, including the paraventricular nucleus as well as the olfactory and limbic systems (36,37). These receptors provide potential sites at which changing insulin levels could alter food intake. The delay preceding elevation of insulin levels in the brain implies that increases in insulin in plasma that accompany food intake would be insufficient to modify eating behavior. It is more likely that regulation of food intake by insulin-receptor binding in the brain represents a long-term response to changes in adipose tissue mass. Hyperinsulinemia is well documented in obese animals and human beings. Despite elevation of insulin levels in plasma, however, several studies show a decrease in the insulin content in the brain of genetically obese Zucker rats (38,39). This research suggests that in some genetically predisposed individuals, insulin may fail to gain access to sites in the brain at which insulin-receptor binding inhibits feeding. Other researchers have reported unchanged (40,41) or slightly increased insulin-receptor binding (42) in the brains of obese rodents. These results imply that continued eating and obesity are the results of postreceptor defects. Although impairment of this insulin-mediated mechanism may explain obesity in patients with a specific genetic predisposition, not all obesity is genetically determined. Weight gain may be the result of excessive eating in response to cognitive or environmental stimuli. When such individuals restrict their dietary intake, insulin levels in plasma would be expected to fall as a consequence of reduced food intake and decreasing adipose tissue mass. Some studies (43-45) suggest that declining plasma insulin levels in food-restricted rodents act specifically to increase hypothalamic concentrations of neuropeptide Y,a potent stimulator of food intake (46). Thus, neuropeptide Y may play a part in preserving body fat stores in dieters, which explains why permanent weight loss is so difficult to achieve. Other indicators of fat metabolism may also influence food intake. 3-Hydroxybutyrate, a product of fat catabolism, appears to mediate satiety by decreasing the activity of the hepatic vagal sensory system (12,47). Prostaglandins synthesized from fatty acid precursors in adipose tissue circulate in the blood in proportion to adipose tissue mass in rats and inhibit food intake by decreasing rates of chemical and physical digestion (48). However, prostaglandins also interact with chemical regulators in the brain, suppressing food intake induced by endogenous opioids and norepinephrine (49). Thus their actions not only reinforce the effects of gastrointestinal peptides released during feeding, but they also oppose central feeding mechanisms operating in the brain. Inhibition of Feeding by the Central Nervous System Carbohydrate ingestion, by increasing insulin levels in plasma, plays a part in the synthesis of feeding-inhibitory chemical regulators, including the neurotransmitter serotonin. Insulin secretion increases the uptake of most amino acids into muscle tissue, but tryptophan, the precursor of serotonin, remains in the blood, where its concentration rises relative to other amino acids (50). Because tryptophan must compete with these amino acids for transport by a nonselective carrier across the blood-brain barrier, its entry into the brain and conversion to serotonin is accelerated by insulin. The high concentration of serotonin in the brain and its presence in enterochromaffin cells of the intestine (51) suggest that serotonin may decrease food intake by modifying both central and peripheral mecha-
nisms of feeding control. Within the brain, serotonin is concentrated in the paraventricular nucleus, which also contains high concentrations of norepinephrine and the opioid 3-endorphin (52). The central effects of serotonin may parallel those of prostaglandins in suppressing food intake by inhibiting norepinephrine- and/or opioid-induced feeding. Serotonin concentrations are significantly decreased by administration of neuropeptide Y to the ventromedial hypothalamus and the lateral hypothalamus (53), and the ability of neuropeptide Y to increase food intake may be mediated by a reduction in serotonin concentration in the brain. The serotoninergic drugs D-fenfluramine and fluoxetine prolong the effects of serotonin by inhibiting its reuptake into presynaptic neurons; these drugs have been used with some success to control food intake in obese human beings. D-Fenfluramine decreases carbohydrate snacking in carbohydrate-craving obese subjects without affecting fat or protein intake (14). Subjects participating in a combined behavior therapy and fenfluramine weight reduction program showed significantly greater weight loss than subjects undergoing behavior therapy alone (54). However, withdrawal of the drug was followed by weight gain. More recently, two 1-year controlled studies have demonstrated that fluoxetine decreases body weight in obese subjects (55,56). In both cases, the effectiveness of drug therapy was significantly higher during the first 6 months; subjects showed either slowing of their rate of weight loss (55) or weight gain (56) during the latter part of the fluoxetine treatment regimen. Stimulation of Feeding by the Central Nervous System The inhibition by prostaglandins and serotonin of feeding induced by opioids and norepinephrine in the paraventricular nucleus, and the sensitivity of the paraventricular nucleus to the satiating effect of bombesin (21), suggest that opioids and norepinephrine are the principal central chemical regulators stimulating food intake. The ability of opioids and norepinephrine to enhance ingestion of fats and carbohydrates, respectively (15,16), implies that their activities are related to homeostatic control of energy balance. Nevertheless, opioids and norepinephrine are colocalized in the brain with other stimulatory chemical regulators and probably interact with these regulators and with neural pathways to enhance feeding. Opioids are directly implicated in feeding control by their presence in the brain at concentrations that vary with food availability and dietary composition (2). They influence food intake by binding at specific receptor sites and modulating neurotransmitter synthesis. Activation of opioid receptors on the terminals of dopaminergic fibers in the nigrostriatal tract increases synthesis of the catecholamine neurotransmitter dopamine, which initiates feeding. The opioid dynorphin is a potent stimulator of feeding (52), and naloxone, an opioid antagonist, blocks eating induced by dynorphin (57). Endorphin, although less potent than dynorphin (52), is elevated in the plasma of obese females (58); this observation is consistent with a chemical role for 3-endorphin in feeding control. The opioid antagonist naltrexone has been shown to decrease the amount of food consumed by obese human beings at a single meal (59), but long-term trials with this drug failed to produce significant weight loss in obese subjects (59-61). Because 3-endorphin and norepinephrine are colocalized in the paraventricular nucleus and both depress neural activity in this region (62), they may induce eating by suppressing feeding-inhibitory neurons. The noradrenergic receptor blocker phentolamine antagonizes both norepinephrine- and opioid-induced eating, whereas opioid antagonists fail to diJOURNAL OF THE AMERICAN DIETETIC ASSOCIATION / 453
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minish norepinephrine-induced eating. According to the study of Leibowitz and Hor (62), the noradrenergic system stimulates eating independently of opioid receptors, whereas -endorphin requires intact noradrenergic receptors to mediate control of food intake. The role of -endorphin in eating appears, therefore, to be an indirect one, and this may explain why use of opioid antagonists has met with limited success in weight control. The paraventricular nucleus is the primary site at which norepinephrine elicits feeding, and isolation of the gastrointestinal peptides galanin and neuropeptide Y from this site implies that interaction among these three chemical regulators stimulates eating. Galanin, however, produces a dose-dependent increase in carbohydrate and fat consumption (18), and because norepinephrine specifically increases carbohydrate consumption, different mechanisms are probably used to increase food intake. Physiologic doses of neuropeptide Y enhance carbohydrate intake (17) and prolong vasoconstriction of cerebral arteries affected by norepinephrine (63), which suggests that restrictions in blood and nutrient flow to the hypothalamus could mediate perception of hunger by the central nervous system. However, although adrenalectomy negates norepinephrine-induced feeding (64), the effect of neuropeptide Y on food intake remains unchanged (65) and neuropeptide Y,like galanin, probably elicits feeding independently of norepinephrine. The ability of neuropeptide Y to overcome the effect of cholecystokinin (17), a potent peripheral mediator of satiety, suggests that this peptide is an important mediator of eating behaviors in the central nervous system. APPLICATIONS Physiologic control of eating is apparently mediated by neural and chemical regulators operating within the brain and in peripheral structures, including the gut, liver, and adipose tissue. The coordination of food intake by multiple neurotransmitters in the paraventricular nucleus suggests that a complex control system with built-in fail-safe devices exists for the primary purpose of ensuring survival of the individual by satisfying energy requirements. The mediation of carbohydrate intake by norepinephrine, galanin, and neuropeptide Y illustrates this concept. The presence of alternative central chemical mediators of food intake implies that those forms of obesity with a physiologic basis may result from malfunction of one or more of the multiple components of food intake control. Suppression of food intake in these obese patients depends on accurate diagnosis of the malfunctioning component(s) and selection of one or more appropriate therapeutic agents to compensate for the defect(s). The hypothalamus plays a pivotal role in integrating the neural and chemical pathways that mediate hunger and satiety. Success in alleviating obesity by pharmacologic means will probably depend on altering some aspect of hypothalamic function. Gastrointestinal peptides and serotoninergic agents influence hypothalamic events, and drugs representing each of these categories have been used for weight control. The efficacy of cholecystokinin and bombesin in short-term weight reduction has been documented (27,28), but their ability to regulate eating on a long-term basis without significant side effects remains to be determined. The serotoninergic agents fenfluramine and fluoxetine have produced weight loss in obese patients participating in trials lasting up to 1 year (14,54-56). Although both drugs have shown no significant side effects in short-term studies (66,67), patients usually regain weight when drug therapy is discontinued. In addition, the safety and efficacy of the drugs in regimens exceeding 1 year in duration have yet to be evaluated. 454 / APRIL 199:. VOLUME 93 NUMBER 4
If effective therapy is to be implemented for patients whose obesity is the consequence of physiologic imbalance, studies must address the issues of optimum duration of drug treatment for weight reduction and minimization of side effects. To date, strategies for achieving weight reduction have been applied on the premise that obesity is an acute disorder requiring shortterm intervention. The finding that termination of serotoninergic drug therapy is accompanied by weight regain suggests that a more realistic approach to weight control may be to regard obesity as a chronic condition in need of ongoing management. Carefully monitored clinical studies are needed to determine whether permanent weight control in such patients requires maintenance on an intermittent or continuous regimen with one or more therapeutic agents. References 1. Anand BK, Brobeck JR. Hypothalanmic control of food intake in rats and cats. Yale JBiolMed. 1951; 24:123-140. 2. Fibiger HC, Zis AP, McGreer EG. Feeding and drinking deficits after 6-hydroxytryptamine administration in the rat: similarities to the lateral hypothalamic syndrome. Brain Res. 1973; 55:135-148. 3. Ricardo JA, Koh ET. Anatomical evidence of direct projections from the nucleus of the solitary tract to the hypothalamus, amygdala and other forebrain structures in the rat. Brain Res. 1978; 153:1-26. 4. Hyde TM, Miselis RR. Effects of area postrema/caudal medial nucleus of solitary tract lesions on food intake and body weight. Am ,I Physiol. 1983; 244:R577-R587. 5. Sawchenko PE. Central connections of the sensory and motor nuclei of the vagus nerve. JAuton Nerv Syst. 183; 9:13-26. 6. Novin D, Robinson K, Culbreth LA, Tordoff MG. Is there a role for the liver in control of food intake? Am I CliniN tr 1985; 42:10501062. 7. Lotter EC, Krinski R, McKay JM, Treneer CM, Porte D, Woods SC. Somatostatin decreases food intake of rats and baboons. . Comnp Physiol Psychol. 1981; 95:278-287. 8. Smith GP, Jerome C, Norgen R. Afferent axons in abdominal vagus mediate satiety effect of cholecystokinin in rats .4rm .J Physiol 1985; 249:R638-R641. 9. Stuckey JA, Gibbs J, Smith GP. Neural disconnection of gut from brain blocks bombesin-induced satiety. Peptides 1985; 6:1249-1252. 10. Woods SC, Porte D, Bobbioni E, lonescu E, Sauter JF, Jeanrenaud FR, Jeanrenaud B. Insulin: its relationship to the central nervous system and to the control of food intake and body weight. Arm J Cli Nutr 1985; 42:1063-1071. 11. Bray GA, Teague RJ, Lee CK. Brain uptake of ketones in rats with differing susceptibility to dietary obesity. Metabolism. 1987; 36:27-30. 12. Arase K, Fisler JS, Shargill NS, York DA, Bray GA. Intracerebroventricular infusions of 3-OHB and insulin in a rat model of dietary obesity.Am J Physiol. 1988; 255:R974-R981. 13. Orthen-Gambill N, Kanarek RB. Differential effects of amphetamine and fenfluramine on dietary self-selection in rats. Pharmu:col Biochem Behav. 1982; 16:303-309. 14. Wurtman J, Wurtman R, Mark S, Tsay R, Gilbert W, Growdon J. fFenfluramine selectively suppresses carbohydrate snacking by obese subjects. Int JEatingDisord. 1985; 4:89-99. 15. Marks-Kaufman R, Kanarek RB. Morphine selectively influences macronutrient uptake in the rat. Pharmnacol Biochem Behanr 1980; 12:427-430. 16. Leibowitz SF, Weiss GF, Yee F, Tretter JI. Noradrenergic innervation of the paraventricular nucleus: specific role in control of carbohydrate ingestion. Brain Res Bull. 1985; 14:561-567. 17. Morley JE, Levine AS, Gosnell BA, Kneip .1, Grace M. Effect of neuropeptide Y on ingestive behaviors in the rat. Am .I Physiol. 1987; 252:R599-R609. 18. Kyrkouli SE, Stanley BG, Leibowitz SF. Galanin: stimulation of feeding induced by medial hypothalamic injection of this novel peptide. EurJPharmacol.1986; 122:159-160. 19. Gyr K, Beglinger C, Kohler E, Trautzl U, Keller U, Bloom SR. Circulating somatostatin-physiological regulator of pancreatic function? .J Clin Invest. 1987; 79:1595-1600 (iontin.aed on page 457
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After reading the continuing education article, "Physiologic control of food intake by neural and chemical mechanisms," please answer the following questions by indicating your responses on the self-assessment questionnaire form located on the next page. This activity has been approved for 1 hour of continuing education credit for registered dietitians and dietetic technicians, registered, by the Commission on Dietetic Registration. Answers to the self-assessment questionnaire can be found on page 512. ADA members should cut out the completed form and return it, with a check for $12 each (nonmembers $16) to cover processing, to: The American Dietetic Association, PO Box 97215, Chicago, IL 60678-7215. Questionnaires must be returned within 1 year of their appearance in the Journalin order to be eligible for credit. Notification will not be sent if hour is approved.
3. What specific event, according to the authors, stimulates the release of the gastrointestinal peptides? A. Absence of food in the gut B. Electrical stimulation of vagal sensory fibers C. Elevated levels of hepatic glucose D. Increased levels of plasma insulin E. Presence of food in the gut
ITEMS 1 TO 4 For items 1 to 4, select the one best answer or completion to each question or incomplete statement.
ITEMS 5 TO 7 For items 5 to 7, select all completions that are true. Each item may have one, two, three, or four correct answers.
1. The authors contend that the physiologic control of eating behaviors via specific neural mechanisms is best viewed in which manner on the basis of current research findings? A. Central mechanisms of the brain and sensory input to the brain from peripheral structures regulate eating B. Central mechanisms operating in the brain help regulate eating, but sensory input to the brain from peripheral structures has more impact C. Hypothalamus is the sole regulator of eating D. Neural mechanisms operating in other regions of the brain have as much impact in regulating eating as does the hypothalamus E. Sensory input to the brain from peripheral structures is the primary regulator of eating
5. Principal chemical stimulators of satiety indicated by the authors include: A. Hepatic glucose concentration B. Plasma insulin C. Prostaglandins D. Serotonin
2. Where are the principal chemical regulators of eating localized, according to the authors? A. Gut B. Lateral hypothalamus C. Nucleus of the tractus solitarius D. Paraventricular nucleus E. Vagal sensory system
4. The authors indicate that serotoninergic agents without significant short-term side effects but with unknown safety and efficacy in regimens lasting more than 1 year include: A. D-fenfluramine (Pondimin) B. Fluoxetine (Prozac) C. Both A and B above D. Neither A nor B above
6. Principal neural stimulators of satiety designated by the authors include: A. Lateral hypothalamus B. Nucleus of the tractus solitarius C. Paraventricular nucleus D. Ventromedial hypothalamus 7. Principal chemical stimulators of hunger delineated by the authors include: A. Brain insulin B. Galanin C. Opioids D. Somatostatin
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ITEMS 8 TO 18 Mechanisms of actionfor chemical regulatorsof eating A. Bombesin B. Galanin C. Hepatic glucose D. Insulin (plasma) E. Norepinephrine F. Opioids G. Prostaglandins H. Somatostatin I. 3-Hydroxybutyrate
10. Produces a dose-dependent increase in carbohydrate and fat consumption
For each mechanism of action with respect to eating behavior listed below, select the chemical regulator that is most likely associated with it. Each option maybe used once, more than once, or not at all.
14. Accelerates conversion of tryptophan into serotonin 15. Decreases food intake by inhibiting activity of hepatic vagal sensory system
8. A product of fat metabolism that may regulate food intake and body weight
16. Decreases frequency of eating and meal size regardless of the integrity of the vagal sensory system
9. Capable of invoking a satiating effect both peripherally and by direct action on the central mechanisms operating in the brain
17. Circulates in blood in proportion to adipose tissue mass and inhibits food intake by decreasing rate of chemical and physical digestion
11. Increases preference for sweet and non-sweet carbohydrates 12. Invokes satiety by activating via electrical stimulation the neural mechanisms in the ventromedial hypothalamus 13. Inhibits secretion of pancreatic digestive juices and decreases rate of digestion
18. Preferentially stimulates ingestion of fatty foods CONTINUING -EDUCATION REPORTING FORM-------------------------------CONTINUING EDUCATION REPORTING FORM Continuing Education Article "Physiologic control of food intake by neural and chemical mechanisms," Journal, April 1993
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Continuedfrom page 454 20. Geary N, Smith GP. Selective hepatic vagotomy blocks pancreatic glucagon's satiety effect. Physiol Behav. 1983; 31:391-394. 21. Kyrkouli SE, Stanley BG, Leibowitz SF. Bombesin-induced anorexia: sites of action in the rat brain. Peptides.1987; 8:237-241. 22. De Beaurepaire R, Suaudeau C. Anorectic effect of calcitonin, neurotensin and bombesin infused in the area of the rostral part of the nucleus of the tractus solitarius in the rat. Peptides. 1988; 9:729733. 23. Lewis LD, Williams JA. Regulation of cholecystokinin secretion by food, hormones and neural pathways in the rat. Am J Physiol. 1990; 258:G512-G518. 24. Delong AJ, Klamer M, Jansen JB, Lamers CB. Effect of plasma gastrin, cholecystokinin and pancreatic polypeptide in man. Regul Pept. 1987; 17:285-293. 25. LeSauter J, Geary N. Redundant vagal mediation of the synergistic satiety effect of pancreatic glucagon and cholecystokinin in sham feeding rats. JAuton Nerv Syst. 1990; 30:13-22. 26. Hinton V, Rosofsky M, Granger J, Geary N. Combined injection potentiates the satiety effects of pancreatic glucagon, cholecystokinin and bombesin. Brain Res Bull. 1986; 17:615-619. 27. Murrahainen NE, Kissileff HR, Thornton J, Pi-Sunyer FX. Bombesin: another peptide that inhibits feeding in man. Soc Neurosci (Abstr). 1983; 9:183-186. 28. Stacher GH, Steinringer G, Schmierer G, Schneider C, Winklehner S. Cholecystokinin octapeptide decreases intake of solid food in man. Peptides. 1982; 3:133-136. 29. MacIsaac L, Geary N. Partial denervation dissociates the inhibitory effects of pancreatic glucagon and epinephrine on feeding. Physiol Behav. 1985; 35:233-237. 30. Smith GP, Jerome C, Gibbs J. Abdominal vagotomy does not block satiety effects of bombesin in rats. Peptides. 1981; 2:409-411. 31. Smith GP, Jerome C, Cushin BJ, Eterno R, Simansky KJ. Abdominal vagotomy blocks satiety effects of cholecystokinin in rats. Science. 1981; 213:1036-1037. 32. Shimizu N, Oomura Y,Novin D, Grijalva CV, Cooper PH. Functional correlations between lateral hypothalamic glucose-sensitive neurons and hepatic portal glucose-sensitive units in rats. Brain Res. 1983; 265:49-54. 33. Harris RBS, Martin RJ. Lipostatic theory of energy balance: concepts and signals. Nutr Behav. 1984; 1:253-275. 34. De Jong A, Strubbe JH, Steffens AB. Hypothalamic influence on insulin and glucagon release in the rat. Am, JPhysiol. 1977; 233:E380E388. 35. Schwartz MW, Sipols A, Kahn SE, Latteman DF, Jaborsky GJ, Bergman RN, Woods SC, Porte D Jr. Kinetics and specificity of insulin uptake from plasma into cerebrospinal fluid. Am J Physiol. 1990; 259:E378-E383. 36. Corp ES, Woods SC, Porte D Jr, Dorsa DM, Figlewicz DP, Baskin DG. Localization of 1251-insulin binding sites in the rat hypothalamus by quantitative autoradiography. Neurosci Lett. 1986; 70:17-22. 37. Hill J, Lesniak M, Pert C, Roth J. Autoradiography localization of insulin receptors in rat brain: prominence in olfactory and limbic areas. Neuroscience. 1986; 17:1127-1138. 38. Baskin DG, Stein LJ, Ikeda H, Woods SC, Figlewicz DP, Porte D Jr, Greenwood MRC, Dorsa DM. Genetically obese Zucker rats have abnormally low brain insulin content. Life Sci. 1985; 36:627-633. 39. Figelwicz DP, Dorsa DM, Stein LJ, Baskin DG, Paquette T, Greenwood MRC, Woods SC, Porte D Jr. Brain and liver insulin binding is decreased in Zucker rats carrying the 'fa' gene. Endocrinology. 1985; 117:1537-1543. 40. Havrankova J, Roth J, Brownstein M. Concentrations of insulin and insulin receptors in the brain are independent of peripheral insulin levels: studies of obese and streptozotocin treated rodents. J Clin Invest. 1979; 64:636-642. 41. Zahniser NR, Goens MB, Hanaway PJ, Vinych JV. Characterization and regulation of insulin receptors in rat brain. J Neurochem. 1984; 42:1354-1362. 42. Wilcox BJ, Corp ES, Dorsa DM, Figelwicz DP, Greenwood MRC, Woods SC, Baskin DG. Insulin binding in the hypothalamus of lean and genetically obese Zucker rats. Peptides.1989; 10:1159-1164. 43. Corrin SE, McCarthy HD, McKibbin PE, Williams G. Unchanged hypothalamic neuropeptide Yconcentrations in hyperphagic, hypogly-
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cemic rats: evidence for specific metabolic regulation of hypothalamic neuropeptide Y.Peptides. 1991; 12:425-430. 44. Calza L, Giardino L, Battistini N, Zanni M, Galleti S, Protopapa F, Velardo A. Increases of neuropeptide Y-like immunoreactivity in the paraventricular nucleus of fasting rats. Neurosci Lett. 1989; 104:99104. 45. Sahu A, Kalra PS, Kalra SP. Food deprivation and ingestion induce reciprocal changes in neuropeptide Y concentrations in the paraventricular nucleus. Peptides. 1987; 9:83-86. 46. Paez X, Myers RD. Insatiable feeding evoked in rats by recurrent perfusion of neuropeptide Y in the hypothalamus. Peptides. 1991; 12:609-616. 47. Niijima A. Glucose-sensitive afferent nerve fibers in the liver and their role in food intake and blood glucose regulation. J Auton Ner, Syst. 1983; 9:207-220. 48. Scaramuzzi OE, Baile CA, Mayer J. Prostaglandins and food intake in rats. Experientia.1971; 27:256-257. 49. Levine AS, Morley JE. The effect of prostaglandins PGE-2 and PGF-2 alpha on food intake in rats. PharracolBiochern Behav 1981; 15:735-738. 50. Wurtman JJ, Wurtman RJ. Fenfluramine and fluoxetine spare protein consumption while suppressing caloric intake in rats. Science. 1977; 198:1178-1180. 51. Chafetz MD. Nutrition and Neurotransmitters: The Nutrient Bases of Behavior Engelwood Cliffs, NJ: Prentice-Hall; 1990. 52. Gosnell BA, Morley JE, Levine AS. Opioid-induced feeding: location of sensitive brain sites. BrainRes. 1986; 369:177-184. 53. Shimizu H, Bray GA. Effects of neuropeptide Yon norepinephrine and serotonin metabolism in rat hypothalamus in vivo. BrainRes Bull. 1989; 22:945-950. 54. Brownell KD, Stunkard AJ. Couples training, pharmacotherapy and behavior therapy in the treatment of obesity. Arch Gen Psychi.atry 1981; 38:1224-1229. 55. Marcus MD, Wing RR, Ewing L, Kern E, McDermott M, Gooding W. A double-blind, placebo-controlled trial of fluoxetine plus behavior modification in the treatment of obese binge-eaters and non-bingeeaters. Am J Psychiatry. 1990; 147:876-881. 56. Darga LL, Carroll-Michals L, Botsford SJ, Lucas CE'. Fluoxetine's effect on weight loss in obese subjects. Am J Clin Nutr 1991; 54:321 325. 57. Morley JE, Levine AS. Involvement of dynorphin and the kappaopioid receptor in feeding. Peptides. 1983; 4:797-800. 58. Givens JR, Wiedemann E, Anderson RN, Kitabchi AE. Betaendorphin and beta-lipotropin plasma levels in hirsute women: correlation with body weight. J Clin Endocrinol Metab. 1980; 50:975-976. 59. Atkinson RC, Berke LK, Drake CR, Bibbs ML, Williams FL, Kaiser DL. Effects of long-term therapy with naltrexone on body weight in obesity. Clin Pharmacol Ther 1985; 38:419-422. 60. Maggio CA, Presta E, Bracco EF, Vasselli JR, Kissileff HR, Pfohl DN, Hashim SA. Naltrexone and human eating behavior: a dose-ranging inpatient trial in moderately obese men. Brain Res Bull. 1985; 14:657661. 61. Malcolm R, O'Neill PM, Sexauer JD, Riddle E, Currey E, Counts C. A controlled trial of naltrexone in obese humans. Int J Obes. 1985; 9:347-353. 62. Leibowitz SF, Hor L. Endorphinergic and alpha-noradrenergic systems in the paraventricular nucleus: effects on eating behavior. Peptides. 1982; 3:421-428. 63. Gray TS, Morley JE. Neuropeptide Y: anatomical distribution and possible function in mammalian nervous system. L ife Sci. 1986; 38:389401. 64. Bakthavatsalam P, Leibowitz S. Alpha 2-noradrenergic feeding rhythm in the paraventricular nucleus: relation to corticosterone. Am JPhysil. 1986; 250:R83-R88. 65. Levine AS, Morley JE, Grace M, Kneip J. A comparison between neuropeptide Y- and norepinephrine-induced feeding. Fed Proc. 1985; 44:787A. 66. Guy-Grand B, Apfelbaum M, Crepaldi G, Gries A, Lefebvre P, Turner P. International trial of dexfenfluramine in obesity. Lancet. 1989; 2:1142-1144. 67. Wise S. Fluoxetine, efficacy and safety in treatment of obese type 2 (non-insulin-dependent) diabetes. Diabetologia. 1989; 37:557A. Abstract.
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Physiologic control of food intake by neural and chemical mechanisms PHIJPPANORTON, MEd, RD; GRACE FALCIGLIA, EdD, RD; DANIEL GIST,PhD
IUIRMT:
Physiologic control of eating involves neural and chemical regulators that may have therapeutic applications in weight control. Information on the nature and quantity of ingested and stored nutrients is relayed to the brain via sensory nerve fibers. This information is integrated at specific centers in the brain, then impulses in motor nerve fibers are discharged leading to initiation or termination of eating. Chemical regulators of eating behavior include gastrointestinal peptides released during digestion, absorbed glucose circulating in the plasma, and the hormonal regulators of glucose metabolism (insulin and glucagon). There is, however, considerable interplay between neural and chemical processes in regulation of food intake. Neural mechanisms are evidently mediated by chemical regulators, because neurotransmitters, including serotonin, allow nerve impulses to cross synapses. In addition, some chemical regulators are concentrated at brain centers that are implicated in regulation of eating behavior. Although some gastrointestinal peptides and serotoninergic drugs have been used to treat obesity, the existence of a complex control system with alternate mediators of food intake suggests that a single therapeutic agent is unlikely to be applied universally to suppress overeating. JAm Diet Assoc. 1993; 93:450-454, 457.
any factors have been implicated in the etiology of obesity; cognitive, environmental, and genetic influences have been widely investigated. For some obese patients, however, eating behavior and body weight may be the consequence of a physiologic impairment. Although numerous studies have probed the physiologic factors that influence eating behavior, details of the neural and chemical processes involved in eating and satiety have yet to be integrated into a model that accurately represents the regulation of food intake. An understanding of these endogenous mechanisms is vital if effective therapies are to be developed for the purpose of weight control in patients whose obesity is the result of physiologic imbalance. In this article we review briefly the neural mechanisms and chemical regulators involved in controlling food intake. Then we describe how these two sets of physiologic signals are integrated to initiate or terminate eating. Finally, we address the possibility of using the physiologic effects of chemical regulators for therapeutic purposes. NEURAL MECHANISMS Role of the Brain in Regulation of Eating Behavior The lateral hypothalamus and the ventromedial hypothalamus were assigned the roles of feeding center and satiety center, respectively, on the basis of early lesion experiments in laboratory animals (1). More recently, anatomic studies and electrophysiologic techniques have been used to investigate the roles of regions outside of the hypothalamus in eating behavior. Figure 1 shows some of the regions of the brain implicated in the control of eating. An association has been demonstrated between the lateral hypothalamus and the nigrostriatal tract: destruction of the latter leads to hypophagia and weight loss (2). The paraventricular nucleus of the hypothalamus is connected to a region in the dorsal medullathe nucleus of the tractus solitarius-destruction of which also results in hypophagia and weight loss in rats (3,4). Thus, eating is not influenced solely by the hypothalamus but also by neural mechanisms operating in other regions of the brain. P. Norton (correspondingauthor) was a graduate research assistantin the Department of Health and Nutrition Sciences at the University of Cincinnati, Cincinnati, OH 45221 at the time of the study; she is currently a renal dietitianwith Dialysis Clinic, Inc, Cincinnati, OH 45206. G. Falcigliais an associate professor of nutritionin the Department of Health and Nutrition Sciences and D. Gist is an associateprofessor iia the Department of BiologicalSciences at the Universit/ (?/ Cincinnati.
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Sensory Input to the Brain Via the vagus nerve, the brain receives sensory information about rates of digestion in the gut and metabolism of nutrients in the liver (5). An increase in glucose content of liver cells after a meal changes the frequency of impulses reaching the nucleus of the tractus solitarius in vagal sensory nerve fibers (6). Autoradiographs show nerve tracts ascending from the nucleus and presumably carrying sensory information from the vagus nerve to the hypothalamus and components of the limbic system in the forebrain (3). Nerve tracts projecting from the hypothalamus and limbic system to vagal motor nerve fibers of the autonomic nervous system via the nucleus of the tractus solitarius (5) may be important motor components of eating behavior. Thus, eating is regulated not only by central mechanisms operating in the brain but also by sensory input to the brain from peripheral structures. CHEMICAL REGULATORS Peripheral Chemical Regulators The presence of food in the gut stimulates the release of gastrointestinal peptides such as somatostatin, cholecystokinin, glucagon, and bombesin, all of which produce a dosedependent decrease in meal size (7-9). Plasma levels of insulin are positively correlated with body fat stores (10), which suggests that body weight may be another factor controlling eating behavior. A product of fat catabolism, 3-hydroxybutyrate, crosses the blood-brain barrier at a higher rate in rats resistant to dietary obesity compared with a strain that is susceptible to obesity (11). Infusion of 3-hydroxybutyrate into the rat brain has also been shown to decrease food intake and body weight (12). Products of fat catabolism may, therefore, be involved in regulating food intake and body weight. Neurotransmitters Chemical regulators synthesized in the brain from assimilated nutrients play a part in controlling eating behavior. For example, accelerated entry of tryptophan into the brain after carbohydrate consumption and insulin secretion promotes synthesis of serotonin, a neurotransmitter implicated in suppression of carbohydrate consumption in rats and obese human beings (13,14). Chemical regulators that increase ingestion of specific, highenergy nutrients are present in the brain. Opioids preferentially stimulate the ingestion of fatty foods (15). Norepinephrine, in contrast, increases preference for sweet and nonsweet carbohydrates in rats (16). Other central feeding-stimulatory chemicals involved in mediating intake of high-energy nutrients include neuropeptide Y (17) and galanin (18). INTEGRATION OF NEURAL MECHANISMS AND CHEMICAL REGULATORS The preceding discussion suggests that mechanisms regulating food intake are activated by a series of neural and chemical signals. The Table summarizes the signals that mediate hunger and satiety These signals, which simultaneously indicate the quantity of ingested food in the gut and the body's requirements for energy, must be integrated to initiate or terminate feeding. Thus, control centers in the brain may direct eating behavior on the basis of information received in the form of nerve impulses and chemical stimuli arising in peripheral tissues. Interactions between neural and chemical signals originating in the brain and peripheral structures are shown in Figure 2. Control of food intake as a result of integration of neural and chemical signals will be the focus of the remainder of this article.
FIG 1. Regions of the brain implicated in regulationof food intake and neuralconnections between them.
Table Principal neural and chemical stimulators of hunger and satiety Hunger Neural Lateral hypothalamus Limbic system Nigrostriatal tract Nucleus of the tractus solitarius Paraventricular nucleus Chemical Dopamine Galanin Insulin (plasma) Neuropeptide Y Norepinephrine Opioids
Satiety Nucleus of the tractus solitarius Paraventricular nucleus Ventromedial hypothalamus
Bombesin Cholecystokinin Insulin (brain) Glucagon Hepatic glucose concentration 3-Hydroxybutyrate Prostaglandins Serotonin Somatostatin
Gastrointestinal Peptides The presence of food in the gut stimulates release of gastrointestinal peptides. These peptides can either enter the circulatory system and ultimately interact with specific centers in the brain or elicit an effect at one or more peripheral sites; satiety signals are relayed via sensory nerve fibers to the brain. Somatostatin is a peripheral mediator of satiety because meal size is decreased by infusion of the peptide into the peritoneal cavity but not by direct administration to the brains of laboratory animals (7). The peripheral action of somatostatin is likely to extend to human beings because intravenous infusion of postprandial concentrations of this peptide inhibit secretion of pancreatic digestive juices in human subjects (19) and presumably decrease the rate of digestion. JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION / 451
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Results of animal studies imply that the satiating effect of cholecystokinin and glucagon is mediated peripherally because food intake is diminished only when vagal sensory fibers are intact (8,20). If these peptides acted directly on the brain, food intake would also decrease in animals subjected to neural disconnection of the brain and gut. Bombesin, like cholecystokinin, decreases meal size in rats only when vagal sensory fibers are intact. However, bombesin also decreases the frequency of eating, and this effect is observed regardless of the integrity of the vagal sensory fibers (9). Bombesin may, therefore, elicit satiety both peripherally and by direct action on the brain. Further evidence of this effect is provided by the decrease in food intake brought about by infusion of bombesin into the lateral hypothalamus, paraventricular nucleus, and nucleus of the tractus solitarius (21,22). Bombesin stimulates release of cholecystokinin in animals and human beings (23,24), and the satiating effect of cholecystokinin in rats is increased by glucagon (25). These results suggest that gastrointestinal peptides may act synergistically to regulate eating behavior, and cholecystokinin, bombesin, and glucagon have indeed been shown to interact in this way to reduce meal size in rats (26). Infusions of bombesin and cholecystokinin have been demonstrated to decrease eating in human beings (27,28), which raises the possibility that gastrointestinal peptides may have therapeutic applications in weight control. Inhibition of food intake by these agents is accompanied, however, by mild abdominal distress. In addition, the issues of long-term safety and efficacy in weight management remain to be addressed. Furthermore, animal experiments have demonstrated that the gastrointestinal peptides signal satiety via different vagal sensory pathways (29-31), suggesting that separate peripheral satiety signals generated by different peptides are integrated in the brain. If this is the case, an opportunity exists for stimuli generated by other central and peripheral satiety mechanisms to interact with and either reinforce or override the signals generated by gastrointestinal peptides. 452 / APRIL 1993 VOLUME 93 NUMBER 4
Hepatic Glucose Metabolism Eating behavior may be modified by autonomic responses in peripheral structures, including the gut and liver. The liver is the immediate destination for end products of digestion absorbed into the hepatic portal system and a storage depot for carbohydrates. Therefore, the liver has the potential to influence ingestive behavior in response to glucose intake and storage. Uptake of glucose by the liver after a meal suppresses the vagal sensory system and decreases the activity of glucosesensitive neurons in the lateral hypothalamus (32). The ventromedial hypothalamus also contains neurons that are sensitive to hepatic glucose concentration, and glucose ingestion increases electrical activity in this region, which leads to satiety (33). Thus, an increase in the amount of glucose absorbed from the gut appears to activate neural mechanisms that may be involved in meal termination. The same neural areas are also implicated in the release of chemical regulators of glucose metabolism. When food is ingested, increases in plasma concentrations of glucagon and insulin precede glucose absorption (34). Electrical stimulation of the ventromedial hypothalamus and lateral hypothalamus also elicits glucagon and insulin secretion, so output of these chemical regulators by the pancreas appears to be a reflex response mediated by hypothalamic nuclei. Adipose Tissue Mass Studies with fasting human beings have shown a positive correlation between insulin levels in plasma and the size of body fat stores (10), and insulin, acting as an index of adiposity, might be expected to play a part in regulating food intake. However, many physiologic processes, including food intake, affect plasma insulin levels. A physiologic increase in insulin in plasma is followed, after an initial lag, by significant elevation of insulin in the cerebrospinal fluid (35). Because cerebrospinal fluid is believed to be formed largely from interstitial fluid in the brain, the appear-
ance of insulin in cerebrospinal fluid must be preceded by entry of insulin from the plasma into the brain. Autoradiographs have demonstrated concentrations of insulin receptors in specific hypothalamic regions associated with food intake, including the paraventricular nucleus as well as the olfactory and limbic systems (36,37). These receptors provide potential sites at which changing insulin levels could alter food intake. The delay preceding elevation of insulin levels in the brain implies that increases in insulin in plasma that accompany food intake would be insufficient to modify eating behavior. It is more likely that regulation of food intake by insulin-receptor binding in the brain represents a long-term response to changes in adipose tissue mass. Hyperinsulinemia is well documented in obese animals and human beings. Despite elevation of insulin levels in plasma, however, several studies show a decrease in the insulin content in the brain of genetically obese Zucker rats (38,39). This research suggests that in some genetically predisposed individuals, insulin may fail to gain access to sites in the brain at which insulin-receptor binding inhibits feeding. Other researchers have reported unchanged (40,41) or slightly increased insulin-receptor binding (42) in the brains of obese rodents. These results imply that continued eating and obesity are the results of postreceptor defects. Although impairment of this insulin-mediated mechanism may explain obesity in patients with a specific genetic predisposition, not all obesity is genetically determined. Weight gain may be the result of excessive eating in response to cognitive or environmental stimuli. When such individuals restrict their dietary intake, insulin levels in plasma would be expected to fall as a consequence of reduced food intake and decreasing adipose tissue mass. Some studies (43-45) suggest that declining plasma insulin levels in food-restricted rodents act specifically to increase hypothalamic concentrations of neuropeptide Y,a potent stimulator of food intake (46). Thus, neuropeptide Y may play a part in preserving body fat stores in dieters, which explains why permanent weight loss is so difficult to achieve. Other indicators of fat metabolism may also influence food intake. 3-Hydroxybutyrate, a product of fat catabolism, appears to mediate satiety by decreasing the activity of the hepatic vagal sensory system (12,47). Prostaglandins synthesized from fatty acid precursors in adipose tissue circulate in the blood in proportion to adipose tissue mass in rats and inhibit food intake by decreasing rates of chemical and physical digestion (48). However, prostaglandins also interact with chemical regulators in the brain, suppressing food intake induced by endogenous opioids and norepinephrine (49). Thus their actions not only reinforce the effects of gastrointestinal peptides released during feeding, but they also oppose central feeding mechanisms operating in the brain. Inhibition of Feeding by the Central Nervous System Carbohydrate ingestion, by increasing insulin levels in plasma, plays a part in the synthesis of feeding-inhibitory chemical regulators, including the neurotransmitter serotonin. Insulin secretion increases the uptake of most amino acids into muscle tissue, but tryptophan, the precursor of serotonin, remains in the blood, where its concentration rises relative to other amino acids (50). Because tryptophan must compete with these amino acids for transport by a nonselective carrier across the blood-brain barrier, its entry into the brain and conversion to serotonin is accelerated by insulin. The high concentration of serotonin in the brain and its presence in enterochromaffin cells of the intestine (51) suggest that serotonin may decrease food intake by modifying both central and peripheral mecha-
nisms of feeding control. Within the brain, serotonin is concentrated in the paraventricular nucleus, which also contains high concentrations of norepinephrine and the opioid 3-endorphin (52). The central effects of serotonin may parallel those of prostaglandins in suppressing food intake by inhibiting norepinephrine- and/or opioid-induced feeding. Serotonin concentrations are significantly decreased by administration of neuropeptide Y to the ventromedial hypothalamus and the lateral hypothalamus (53), and the ability of neuropeptide Y to increase food intake may be mediated by a reduction in serotonin concentration in the brain. The serotoninergic drugs D-fenfluramine and fluoxetine prolong the effects of serotonin by inhibiting its reuptake into presynaptic neurons; these drugs have been used with some success to control food intake in obese human beings. D-Fenfluramine decreases carbohydrate snacking in carbohydrate-craving obese subjects without affecting fat or protein intake (14). Subjects participating in a combined behavior therapy and fenfluramine weight reduction program showed significantly greater weight loss than subjects undergoing behavior therapy alone (54). However, withdrawal of the drug was followed by weight gain. More recently, two 1-year controlled studies have demonstrated that fluoxetine decreases body weight in obese subjects (55,56). In both cases, the effectiveness of drug therapy was significantly higher during the first 6 months; subjects showed either slowing of their rate of weight loss (55) or weight gain (56) during the latter part of the fluoxetine treatment regimen. Stimulation of Feeding by the Central Nervous System The inhibition by prostaglandins and serotonin of feeding induced by opioids and norepinephrine in the paraventricular nucleus, and the sensitivity of the paraventricular nucleus to the satiating effect of bombesin (21), suggest that opioids and norepinephrine are the principal central chemical regulators stimulating food intake. The ability of opioids and norepinephrine to enhance ingestion of fats and carbohydrates, respectively (15,16), implies that their activities are related to homeostatic control of energy balance. Nevertheless, opioids and norepinephrine are colocalized in the brain with other stimulatory chemical regulators and probably interact with these regulators and with neural pathways to enhance feeding. Opioids are directly implicated in feeding control by their presence in the brain at concentrations that vary with food availability and dietary composition (2). They influence food intake by binding at specific receptor sites and modulating neurotransmitter synthesis. Activation of opioid receptors on the terminals of dopaminergic fibers in the nigrostriatal tract increases synthesis of the catecholamine neurotransmitter dopamine, which initiates feeding. The opioid dynorphin is a potent stimulator of feeding (52), and naloxone, an opioid antagonist, blocks eating induced by dynorphin (57). Endorphin, although less potent than dynorphin (52), is elevated in the plasma of obese females (58); this observation is consistent with a chemical role for 3-endorphin in feeding control. The opioid antagonist naltrexone has been shown to decrease the amount of food consumed by obese human beings at a single meal (59), but long-term trials with this drug failed to produce significant weight loss in obese subjects (59-61). Because 3-endorphin and norepinephrine are colocalized in the paraventricular nucleus and both depress neural activity in this region (62), they may induce eating by suppressing feeding-inhibitory neurons. The noradrenergic receptor blocker phentolamine antagonizes both norepinephrine- and opioid-induced eating, whereas opioid antagonists fail to diJOURNAL OF THE AMERICAN DIETETIC ASSOCIATION / 453
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minish norepinephrine-induced eating. According to the study of Leibowitz and Hor (62), the noradrenergic system stimulates eating independently of opioid receptors, whereas -endorphin requires intact noradrenergic receptors to mediate control of food intake. The role of -endorphin in eating appears, therefore, to be an indirect one, and this may explain why use of opioid antagonists has met with limited success in weight control. The paraventricular nucleus is the primary site at which norepinephrine elicits feeding, and isolation of the gastrointestinal peptides galanin and neuropeptide Y from this site implies that interaction among these three chemical regulators stimulates eating. Galanin, however, produces a dose-dependent increase in carbohydrate and fat consumption (18), and because norepinephrine specifically increases carbohydrate consumption, different mechanisms are probably used to increase food intake. Physiologic doses of neuropeptide Y enhance carbohydrate intake (17) and prolong vasoconstriction of cerebral arteries affected by norepinephrine (63), which suggests that restrictions in blood and nutrient flow to the hypothalamus could mediate perception of hunger by the central nervous system. However, although adrenalectomy negates norepinephrine-induced feeding (64), the effect of neuropeptide Y on food intake remains unchanged (65) and neuropeptide Y,like galanin, probably elicits feeding independently of norepinephrine. The ability of neuropeptide Y to overcome the effect of cholecystokinin (17), a potent peripheral mediator of satiety, suggests that this peptide is an important mediator of eating behaviors in the central nervous system. APPLICATIONS Physiologic control of eating is apparently mediated by neural and chemical regulators operating within the brain and in peripheral structures, including the gut, liver, and adipose tissue. The coordination of food intake by multiple neurotransmitters in the paraventricular nucleus suggests that a complex control system with built-in fail-safe devices exists for the primary purpose of ensuring survival of the individual by satisfying energy requirements. The mediation of carbohydrate intake by norepinephrine, galanin, and neuropeptide Y illustrates this concept. The presence of alternative central chemical mediators of food intake implies that those forms of obesity with a physiologic basis may result from malfunction of one or more of the multiple components of food intake control. Suppression of food intake in these obese patients depends on accurate diagnosis of the malfunctioning component(s) and selection of one or more appropriate therapeutic agents to compensate for the defect(s). The hypothalamus plays a pivotal role in integrating the neural and chemical pathways that mediate hunger and satiety. Success in alleviating obesity by pharmacologic means will probably depend on altering some aspect of hypothalamic function. Gastrointestinal peptides and serotoninergic agents influence hypothalamic events, and drugs representing each of these categories have been used for weight control. The efficacy of cholecystokinin and bombesin in short-term weight reduction has been documented (27,28), but their ability to regulate eating on a long-term basis without significant side effects remains to be determined. The serotoninergic agents fenfluramine and fluoxetine have produced weight loss in obese patients participating in trials lasting up to 1 year (14,54-56). Although both drugs have shown no significant side effects in short-term studies (66,67), patients usually regain weight when drug therapy is discontinued. In addition, the safety and efficacy of the drugs in regimens exceeding 1 year in duration have yet to be evaluated. 454 / APRIL 199:. VOLUME 93 NUMBER 4
If effective therapy is to be implemented for patients whose obesity is the consequence of physiologic imbalance, studies must address the issues of optimum duration of drug treatment for weight reduction and minimization of side effects. To date, strategies for achieving weight reduction have been applied on the premise that obesity is an acute disorder requiring shortterm intervention. The finding that termination of serotoninergic drug therapy is accompanied by weight regain suggests that a more realistic approach to weight control may be to regard obesity as a chronic condition in need of ongoing management. Carefully monitored clinical studies are needed to determine whether permanent weight control in such patients requires maintenance on an intermittent or continuous regimen with one or more therapeutic agents. References 1. Anand BK, Brobeck JR. Hypothalanmic control of food intake in rats and cats. Yale JBiolMed. 1951; 24:123-140. 2. Fibiger HC, Zis AP, McGreer EG. Feeding and drinking deficits after 6-hydroxytryptamine administration in the rat: similarities to the lateral hypothalamic syndrome. Brain Res. 1973; 55:135-148. 3. Ricardo JA, Koh ET. Anatomical evidence of direct projections from the nucleus of the solitary tract to the hypothalamus, amygdala and other forebrain structures in the rat. Brain Res. 1978; 153:1-26. 4. Hyde TM, Miselis RR. Effects of area postrema/caudal medial nucleus of solitary tract lesions on food intake and body weight. Am ,I Physiol. 1983; 244:R577-R587. 5. Sawchenko PE. Central connections of the sensory and motor nuclei of the vagus nerve. JAuton Nerv Syst. 183; 9:13-26. 6. Novin D, Robinson K, Culbreth LA, Tordoff MG. Is there a role for the liver in control of food intake? Am I CliniN tr 1985; 42:10501062. 7. Lotter EC, Krinski R, McKay JM, Treneer CM, Porte D, Woods SC. Somatostatin decreases food intake of rats and baboons. . Comnp Physiol Psychol. 1981; 95:278-287. 8. Smith GP, Jerome C, Norgen R. Afferent axons in abdominal vagus mediate satiety effect of cholecystokinin in rats .4rm .J Physiol 1985; 249:R638-R641. 9. Stuckey JA, Gibbs J, Smith GP. Neural disconnection of gut from brain blocks bombesin-induced satiety. Peptides 1985; 6:1249-1252. 10. Woods SC, Porte D, Bobbioni E, lonescu E, Sauter JF, Jeanrenaud FR, Jeanrenaud B. Insulin: its relationship to the central nervous system and to the control of food intake and body weight. Arm J Cli Nutr 1985; 42:1063-1071. 11. Bray GA, Teague RJ, Lee CK. Brain uptake of ketones in rats with differing susceptibility to dietary obesity. Metabolism. 1987; 36:27-30. 12. Arase K, Fisler JS, Shargill NS, York DA, Bray GA. Intracerebroventricular infusions of 3-OHB and insulin in a rat model of dietary obesity.Am J Physiol. 1988; 255:R974-R981. 13. Orthen-Gambill N, Kanarek RB. Differential effects of amphetamine and fenfluramine on dietary self-selection in rats. Pharmu:col Biochem Behav. 1982; 16:303-309. 14. Wurtman J, Wurtman R, Mark S, Tsay R, Gilbert W, Growdon J. fFenfluramine selectively suppresses carbohydrate snacking by obese subjects. Int JEatingDisord. 1985; 4:89-99. 15. Marks-Kaufman R, Kanarek RB. Morphine selectively influences macronutrient uptake in the rat. Pharmnacol Biochem Behanr 1980; 12:427-430. 16. Leibowitz SF, Weiss GF, Yee F, Tretter JI. Noradrenergic innervation of the paraventricular nucleus: specific role in control of carbohydrate ingestion. Brain Res Bull. 1985; 14:561-567. 17. Morley JE, Levine AS, Gosnell BA, Kneip .1, Grace M. Effect of neuropeptide Y on ingestive behaviors in the rat. Am .I Physiol. 1987; 252:R599-R609. 18. Kyrkouli SE, Stanley BG, Leibowitz SF. Galanin: stimulation of feeding induced by medial hypothalamic injection of this novel peptide. EurJPharmacol.1986; 122:159-160. 19. Gyr K, Beglinger C, Kohler E, Trautzl U, Keller U, Bloom SR. Circulating somatostatin-physiological regulator of pancreatic function? .J Clin Invest. 1987; 79:1595-1600 (iontin.aed on page 457
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After reading the continuing education article, "Physiologic control of food intake by neural and chemical mechanisms," please answer the following questions by indicating your responses on the self-assessment questionnaire form located on the next page. This activity has been approved for 1 hour of continuing education credit for registered dietitians and dietetic technicians, registered, by the Commission on Dietetic Registration. Answers to the self-assessment questionnaire can be found on page 512. ADA members should cut out the completed form and return it, with a check for $12 each (nonmembers $16) to cover processing, to: The American Dietetic Association, PO Box 97215, Chicago, IL 60678-7215. Questionnaires must be returned within 1 year of their appearance in the Journalin order to be eligible for credit. Notification will not be sent if hour is approved.
3. What specific event, according to the authors, stimulates the release of the gastrointestinal peptides? A. Absence of food in the gut B. Electrical stimulation of vagal sensory fibers C. Elevated levels of hepatic glucose D. Increased levels of plasma insulin E. Presence of food in the gut
ITEMS 1 TO 4 For items 1 to 4, select the one best answer or completion to each question or incomplete statement.
ITEMS 5 TO 7 For items 5 to 7, select all completions that are true. Each item may have one, two, three, or four correct answers.
1. The authors contend that the physiologic control of eating behaviors via specific neural mechanisms is best viewed in which manner on the basis of current research findings? A. Central mechanisms of the brain and sensory input to the brain from peripheral structures regulate eating B. Central mechanisms operating in the brain help regulate eating, but sensory input to the brain from peripheral structures has more impact C. Hypothalamus is the sole regulator of eating D. Neural mechanisms operating in other regions of the brain have as much impact in regulating eating as does the hypothalamus E. Sensory input to the brain from peripheral structures is the primary regulator of eating
5. Principal chemical stimulators of satiety indicated by the authors include: A. Hepatic glucose concentration B. Plasma insulin C. Prostaglandins D. Serotonin
2. Where are the principal chemical regulators of eating localized, according to the authors? A. Gut B. Lateral hypothalamus C. Nucleus of the tractus solitarius D. Paraventricular nucleus E. Vagal sensory system
4. The authors indicate that serotoninergic agents without significant short-term side effects but with unknown safety and efficacy in regimens lasting more than 1 year include: A. D-fenfluramine (Pondimin) B. Fluoxetine (Prozac) C. Both A and B above D. Neither A nor B above
6. Principal neural stimulators of satiety designated by the authors include: A. Lateral hypothalamus B. Nucleus of the tractus solitarius C. Paraventricular nucleus D. Ventromedial hypothalamus 7. Principal chemical stimulators of hunger delineated by the authors include: A. Brain insulin B. Galanin C. Opioids D. Somatostatin
JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION / 455
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SOl$FASEMINT
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ITEMS 8 TO 18 Mechanisms of actionfor chemical regulatorsof eating A. Bombesin B. Galanin C. Hepatic glucose D. Insulin (plasma) E. Norepinephrine F. Opioids G. Prostaglandins H. Somatostatin I. 3-Hydroxybutyrate
10. Produces a dose-dependent increase in carbohydrate and fat consumption
For each mechanism of action with respect to eating behavior listed below, select the chemical regulator that is most likely associated with it. Each option maybe used once, more than once, or not at all.
14. Accelerates conversion of tryptophan into serotonin 15. Decreases food intake by inhibiting activity of hepatic vagal sensory system
8. A product of fat metabolism that may regulate food intake and body weight
16. Decreases frequency of eating and meal size regardless of the integrity of the vagal sensory system
9. Capable of invoking a satiating effect both peripherally and by direct action on the central mechanisms operating in the brain
17. Circulates in blood in proportion to adipose tissue mass and inhibits food intake by decreasing rate of chemical and physical digestion
11. Increases preference for sweet and non-sweet carbohydrates 12. Invokes satiety by activating via electrical stimulation the neural mechanisms in the ventromedial hypothalamus 13. Inhibits secretion of pancreatic digestive juices and decreases rate of digestion
18. Preferentially stimulates ingestion of fatty foods CONTINUING -EDUCATION REPORTING FORM-------------------------------CONTINUING EDUCATION REPORTING FORM Continuing Education Article "Physiologic control of food intake by neural and chemical mechanisms," Journal, April 1993
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Continuedfrom page 454 20. Geary N, Smith GP. Selective hepatic vagotomy blocks pancreatic glucagon's satiety effect. Physiol Behav. 1983; 31:391-394. 21. Kyrkouli SE, Stanley BG, Leibowitz SF. Bombesin-induced anorexia: sites of action in the rat brain. Peptides.1987; 8:237-241. 22. De Beaurepaire R, Suaudeau C. Anorectic effect of calcitonin, neurotensin and bombesin infused in the area of the rostral part of the nucleus of the tractus solitarius in the rat. Peptides. 1988; 9:729733. 23. Lewis LD, Williams JA. Regulation of cholecystokinin secretion by food, hormones and neural pathways in the rat. Am J Physiol. 1990; 258:G512-G518. 24. Delong AJ, Klamer M, Jansen JB, Lamers CB. Effect of plasma gastrin, cholecystokinin and pancreatic polypeptide in man. Regul Pept. 1987; 17:285-293. 25. LeSauter J, Geary N. Redundant vagal mediation of the synergistic satiety effect of pancreatic glucagon and cholecystokinin in sham feeding rats. JAuton Nerv Syst. 1990; 30:13-22. 26. Hinton V, Rosofsky M, Granger J, Geary N. Combined injection potentiates the satiety effects of pancreatic glucagon, cholecystokinin and bombesin. Brain Res Bull. 1986; 17:615-619. 27. Murrahainen NE, Kissileff HR, Thornton J, Pi-Sunyer FX. Bombesin: another peptide that inhibits feeding in man. Soc Neurosci (Abstr). 1983; 9:183-186. 28. Stacher GH, Steinringer G, Schmierer G, Schneider C, Winklehner S. Cholecystokinin octapeptide decreases intake of solid food in man. Peptides. 1982; 3:133-136. 29. MacIsaac L, Geary N. Partial denervation dissociates the inhibitory effects of pancreatic glucagon and epinephrine on feeding. Physiol Behav. 1985; 35:233-237. 30. Smith GP, Jerome C, Gibbs J. Abdominal vagotomy does not block satiety effects of bombesin in rats. Peptides. 1981; 2:409-411. 31. Smith GP, Jerome C, Cushin BJ, Eterno R, Simansky KJ. Abdominal vagotomy blocks satiety effects of cholecystokinin in rats. Science. 1981; 213:1036-1037. 32. Shimizu N, Oomura Y,Novin D, Grijalva CV, Cooper PH. Functional correlations between lateral hypothalamic glucose-sensitive neurons and hepatic portal glucose-sensitive units in rats. Brain Res. 1983; 265:49-54. 33. Harris RBS, Martin RJ. Lipostatic theory of energy balance: concepts and signals. Nutr Behav. 1984; 1:253-275. 34. De Jong A, Strubbe JH, Steffens AB. Hypothalamic influence on insulin and glucagon release in the rat. Am, JPhysiol. 1977; 233:E380E388. 35. Schwartz MW, Sipols A, Kahn SE, Latteman DF, Jaborsky GJ, Bergman RN, Woods SC, Porte D Jr. Kinetics and specificity of insulin uptake from plasma into cerebrospinal fluid. Am J Physiol. 1990; 259:E378-E383. 36. Corp ES, Woods SC, Porte D Jr, Dorsa DM, Figlewicz DP, Baskin DG. Localization of 1251-insulin binding sites in the rat hypothalamus by quantitative autoradiography. Neurosci Lett. 1986; 70:17-22. 37. Hill J, Lesniak M, Pert C, Roth J. Autoradiography localization of insulin receptors in rat brain: prominence in olfactory and limbic areas. Neuroscience. 1986; 17:1127-1138. 38. Baskin DG, Stein LJ, Ikeda H, Woods SC, Figlewicz DP, Porte D Jr, Greenwood MRC, Dorsa DM. Genetically obese Zucker rats have abnormally low brain insulin content. Life Sci. 1985; 36:627-633. 39. Figelwicz DP, Dorsa DM, Stein LJ, Baskin DG, Paquette T, Greenwood MRC, Woods SC, Porte D Jr. Brain and liver insulin binding is decreased in Zucker rats carrying the 'fa' gene. Endocrinology. 1985; 117:1537-1543. 40. Havrankova J, Roth J, Brownstein M. Concentrations of insulin and insulin receptors in the brain are independent of peripheral insulin levels: studies of obese and streptozotocin treated rodents. J Clin Invest. 1979; 64:636-642. 41. Zahniser NR, Goens MB, Hanaway PJ, Vinych JV. Characterization and regulation of insulin receptors in rat brain. J Neurochem. 1984; 42:1354-1362. 42. Wilcox BJ, Corp ES, Dorsa DM, Figelwicz DP, Greenwood MRC, Woods SC, Baskin DG. Insulin binding in the hypothalamus of lean and genetically obese Zucker rats. Peptides.1989; 10:1159-1164. 43. Corrin SE, McCarthy HD, McKibbin PE, Williams G. Unchanged hypothalamic neuropeptide Yconcentrations in hyperphagic, hypogly-
N PRACTGE .....................................
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