Treatment for Obesity: A Nutrient BalancelNutrient Partition Approach George A. Bray, M.D. This paper examines the treatment of obesity, using a feedback model of nutrient regulation. A feedback model contains afferent signals and a central controller that transduces afferent information into efferent signals that modulate the controlled system. Using this model and the receptor hypothesis for drug action, a variety of current and potential therapeutic approaches are discussed. Among the more promising approaches would be cholecystokinin agonists, small molecules that mimic ketoacids, agonists to corticotropin-releasing hormone, beta3 agonists, antagonists to opioid peptides, antagonists to neuropeptide Y, glucocorticoid receptor antagonists, and growth hormone agonists. Since a number of mechanisms can influence body fat and nutrient partitioning, it is likely that optimal therapy will involve use of more than one pharmacologic agent.

elements that tell the controller about the state of the controlled system; and finally, there are the efferent control mechanisms that modulate food intake, physical activity, and nutrient partitioning.

There are several approaches to understanding obesity and modeling its treatment. Behavioral models, metabolic models, and set-point models might be used. This paper presents a homeostatic, or nutrient balance, model for the control of nutrient stores. Obesity can be viewed as a homeostatic failure of this nutrient balance system resulting from a failure of nutrients to stimulate the sympathetic nervous system.' This approach and the receptor hypothesis for drug action may provide a useful system for understanding obesity and the mechanisms for its treatment.

The Controlled System

A Nutrient Balance, Homeostatic Model A regulated, homeostatic or controlled system has several components (Figure 1). First, there is a controller located in the brain. Second, there is a controlled system consisting of intake, digestion, absorption, storage, and metabolism of the nutrients in food. Third, there are feedback or afferent _ _ _ _ _ ~

~

Dr. Bray is Professor of Medicine and Director of the Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana.

c

The normal adult human being contains approximately 140,000 kcal of energy in body fat. This is some six times the quantity of energy stored in protein (24,000 kcal; 100.8 MJ). By comparison, the quantity of carbohydrate is minute, equivalent to only 800 kcal (3.36 MJ), which includes glycogen stores from the liver, kidney, muscle, and other tissues plus the glucose that circulates in the blood. An individual eating 2000 kcal (8.4 MJ) of which 40% is carbohydrate will take in an amount of carbohydrate each day comparable to total body stores. In contrast, average daily protein intake is only a little over 1% of total stores and fat intake is considerably less than 1%. This is shown in Figure 2. It should not be surprising, therefore, that in studies of nutrient balance in experimental animals Flatt2 noted that changes in carbohydrate balance from day to day reciprocally affected carbohydrate intake on the subsequent day. For fat balance, on the other NUTRllIW RffIEWSIVOL Is,NO 2IFEBRUARY 1981 33

CONTROLLER

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Figure 1. A nutrient balance approach to control of focxl intake. The controlled system consists of f w d intake. digestion. storage. and oxidation of nutrient for muscular work and heat production. The afferent signals tell the controller about the state of the controlled system. Efferent systems then regulate the intake and metah)lism of food.

hand, the day-to-day relationship was very weak. There are two major pathways for absorption of digested food from the gut. One of these is through the lacteals, which transport triglycerides packaged as chylomicrons. These enter the venous circulation and are cleared in the periphery by hydrolysis of triglycerides catalyzed by the enzyme lipoprotein lipase. The other pathway for absorption of glucose and amino acids as well as short chain fatty acids is through the portal vein directly to the liver. The nutrients that enter the controlled system can be stored, converted to heat through metabolism, or used for work. In addition, small quantities can be excreted in the urine as end products of the metabolism of amino acids. 34 NUTRITION RfflEWSlVOL 49, NO 2IFEBRUARY 1991

The resting metabolism of human beings is directly related to the amount of fat-free or lean body mass.3 In addition, there is an important familial component in resting energy e~penditure.~ Physical work accounts for approximately one-third the energy expended. A number of studies suggest that body weight and energy stores are well regulated over short intervals in most individuals. For most adults the sensitivity of the system for changes is less than 1% per year. An analysis of this regulatory control system suggests the following concepts: 1. That each major nutrient may be regu-

lated separately. 2. That the time required to achieve balance for each nutrient varies as a function of the amount ingested each day in relation to total body stores of that nutrient. A high-carbohydrate diet is less likely to produce obesity than a high-fat diet because the body storage system for carbohydrate as glycogen is limited. Although excess carbohydrate can be converted to fatty acids, this is an energetically expensive transformation. Body fat stores, on the other hand, are many times larger than daily fat intake, implying a much greater capacity for fat storage and a much longer time constant to achieve balance. 3. That achievement of nutrient balance requires that the net oxidation of each nutrient equal the average composition of the macronutrients in the diet. That is, ingestion of a high-fat diet requires greater oxidation of fat than a low-fat diet when equilibrium is achieved. 4. That there are major differences between individuals in the capacity to increase rapidly the oxidation of fat after beginning a high-fat diet. Much of this difference is genetic. 5. That physical training can increase oxidation of fatty acids by muscle, and thus regular aerobic exercise might reduce the tendency to become obese when eating a high-fat diet. 6. That the regulation of nutrient stores is subject to positive and negative feed-

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Figure 2. The relation of nutrient intake to nutrient stores. A daily intake of 2000 kcal (4.8 MJ)with a distribution of 40% fat, 408 carbohydrate, and 208 fat is shown on the left. The percentage of this daily intake as a percentage of

body stores is shown on the right.

back signals for each component that operates through the central controller. Nutrient intake plays a variable role in the development of obesity in humans and animals. At one extreme there are the types of obesity depicted in Stone Age carvings. Obesity in these people develops regardless of the type of diet available. In these instances genetic factors probably play an important role, since in experimental animals with a genetic tendency to obesity the type of diet is unimportant in its development. At the other extreme there are those types of obesity where diet is central. There are very good data in rats to show that these include a high-fat diet, access to sucrose solutions, and diets with an abundance of highly palatable foods. Any of these types of dietary obesity can be controlled by changing the composition of the diet along with restraint in levels of food intake. These concepts are shown as part of Figure 3. Changing diet composition on the

left can lead to obesity by influencing food intake, energy expenditure, and nutrient partitioning. Even if diet composition does not change, obesity can develop by alterations in the brain or one of the other areas.

Afferent Feedback Signals The brain receives information for regulating nutrient balance from several sources (Figure 1). Afferent signals can be transmitted over the somatic sensory nervous system via the autonomic nervous system or through the bloodstream.

Sensory signals. The sight and smell of food are important afferent signals that identify potential sources of food and initiate food intake. Along with the texture and taste of food in the mouth, sensory cues about the quality of food can serve as posic tive feedback signals to initiate food ingestion as well as negative feedback signals NUTRlTlON REVIEWSIVOL 49, NO BIFEBRUARY 1991 35

AFFERENT SIGNALS

CONTROLLER

EFFERENT SYSTEMS

CONTROLLED SYSTEM (Nutrient Partitioning)

INTAKE

AUTONOMIC NERVOUS SYSTEM COMPOSITION HORMONAL SYSTEMS

PHYSICAL ACTIVITY

Figure 3. A diagram for control o f nutrient partitioning. Changes in diet composition can modify the responses of the brain (controller). The brain. in turn. modulates physical activity. total f t ~ x intake. l the autonomic nervous system. and hormonal secretion to change total fat stores andlor nutrient partitioning between fat and protein.

that eventually slow down, terminate, or abort an eating incident. The ability of most animals to avoid foods that have previously made them sick, a phenomenon known as bait-shyness, is an example of these afferent sensory signals integrated with a central learning system. Gastrointestinal signals. Information from food in the gastrointestinal tract can be initiated by one of three mechanisms: 1) gastrointestinal distension, 2) release of gastrointestinal hormones when nutrients act directly on receptors in the gastrointestinal tract, and 3) through the effects of absorbed nutrients. Both gastric and intestinal distension are mechanisms that terminate meals by negative feedback via the nervous system. The vagus nerve is probably the principal afferent sensory relay for this type of information. Several gastrointestinal hormones have been implicated in the inhibition of feeding. The one studied most prominently is cholecystokinin (CCK).5 lntraperitoneal in-

36 NUTRITION REVIEWSIVOL 49, NO ZIFEBRUARY 1991

jections of CCK decrease food intake in hungry rats and inhibit sham feeding in rats and monkeys. Furthermore, the sequence of events associated with a response to CCK is similar to that of spontaneous postprandial satiety. One suggestion for the effect of CCK is that it acts on antral CCK-A receptors by constricting the pylorus and enhancing gastric distension. This peripheral information generated by CCK may be important in producing ~ a t i e t y since ,~ vagotomy and lesions in the central vagal connections in the nucleus of the tractus solitarius, the ventromedial hypothalamus, and the paraventricular nucleus (PVN) will block the effect of CCK. A second site for action of this peptide may be on CCK-B receptors within the central nervous system itself. CCK is released in the brain during a meal and the injection of CCK into the lateral ventricle and ventromedial hypothalamus and PVN has been reported to reduce food intake.5 Centrally or peripherally released CCK might act on the CCK-B receptors specific to this area. Recent studies by Douclish et aLs suggest

The Controller

that CCK-B receptors in the brain are more important than the Peripheral CCK-A receptors in producing satiety to CCK. Other peptides such as bornbesin' and the N-terminal pentapeptide from ProcoliPasee may also be Signals produced in the gaStrOintestinal tract that inhibit feeding. Nutrient signals. Nutrient signals may also act on the liver or brain to initiate satiety. Glucose injected into the portal circulation decreases the vagal afferent firing rate, probably through acting on hepatic glucose receptors. Glucose may also act directly on the central nervous system for which it is the major source of fuel. Hauger et aLg have demonstrated that glucose affects the interaction of amphetamine with the sodium pumping mechanism in the hypothalamus and that this effect is modulated by the intake of g l u c o ~ e . ~ Fatty acids and their metabolites may also serve as afferent signals to modulate food intake. Peripheral injections of 3-hydroxybutyrate or lactate change the redox potential in the liver and produce satiety.1° Increased fatty acid oxidation by the liver is associated with a decrease in food intake. Lactate might also modulate food intake. Injections of lactate, like 3-hydroxybutyrate, decrease intake. Lactate is produced in adipose tissue, muscle, and other tissues by metabolism of glucose. It is a primary product of glucose oxidation by fat cells and might serve as a metabolic signal from this tissue. Tumors frequently produce a decrease in food intake and weight loss. Tumors might also produce considerable amounts of lactate, which might be anorectic. Finally, metformin and phenformin, two oral drugs that were previously used for treatment of diabetes, increase lactate levels. When compared to sulfonylurea-like drugs, phenformin was more effective at reducing body weight. This might be related to its effect on lactate production. Similarly, the thermogenic effect of caffeine might be related to lactate." The hypothesis that lactate is an afferent signal for satiety requires more testing.

Anatomy. Several anatomic regions of the brain appear to play an important role in the control of nutrient balance (Figure 4). Destruction of the ventromedial hypothalamus is associated with hyperphagia and obesity in most homeothermic species that have been studied.12On the other hand, destruction of the lateral hypothalamus is associated with a decrease in food intake and a reduction in body fat. More recently, the paraventricular nucleus has been shown to be a particularly important region for stimulation of food intake following topical injection of norepinephrine, which acts through a-2-adrenergic receptors. The primacy of the ventromedial nucleus as opposed to the PVN in the regulation of body fat stores is suggested by the fact that chronic infusion of norepinephrine into the vent romedial hypothalamus produces o besity, whereas the infusion of norepinephrine into the PVN does not. This effect may also involve a-2 receptors and has the

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NUTRITION RRIIEWSIVOL 49, NO UFEBRUARY 1991 37

same result as damage of ventromedial hypothalamus neurons. Neurotransmitters. Gamma-amino butyric acid (GABA) is one of the fast-acting neurotransmitters involved in the regulation of food intake.12 In addition to GABA, a number of slow-acting neurotransmitters are involved in modulating intake, including norepinephrine, serotonin, and histamine. Serotonin is a monoamine derived from the dietary amino acid tryptophan. This neurotransmitter reduces food intake by acting on serotonin receptors. Norepinephrine can either decrease food intake by activating p-adrenergic receptors when injected into the perifornical area or stimulate food intake by acting on a-2-adrenergic receptors in the PVN or ventromedial nucleus. A comparison of the tonic level of adrenergic receptor activation in the hypothalamus of genetically obese and lean animals showed that the tonic activity of p-adrenergic receptors was higher and the tonic activity of a-2-adrenergic stimulation was lower in the hypothalamus of lean as compared to obese animals. Thus a shift in the tonic activity from p- to a-2-adrenergic receptors is associated with obesity. This is shown in Figure 4. Histamine is a third monoamine that affects food intake. Activation of H-1 histamine receptors reduces food intake in the ventromedial hypothalamus.13 Several peptides also modulate food inPeptide concentration in the brain is about 0.1-1% that of the monoamines (pg/g vs. ng/g). Neuropeptide Y, p-endorphin, dynorphin, growth-hormone-releasing hormone, and galanin all stimulate food intake when injected into the ventromedial nucleus or PVN. A variety of other peptides, including bombesin, CCK, anortonin, neurotensin, and corticotropin-releasing hormone (CRH) inhibit feeding when injected topically into the region of the ventromedial nucleus or when infused into the third ventricle. One hypothesis to explain the role of neuropeptides in modulation of food intake is through their effects on specific types of 30 NUTRITION REVIEWSIVOL 49, NO ZIFEBRUARY 1991

eating. Thus neuropeptide Y injected into the PVN preferentially increases carbohydrate intake at the beginning of the nocturnal feeding cycle but stimulates fat intake toward the end of the nocturnal eating period. CRH may be an important modulator of stress-related eating. The infusion of insulin into the third ventricle will suppress food intake in animals eating a high-carbohydrate diet but not in animals eating a low-carbohydrate (high-fat) diet.15 These examples suggest that the way in which these peptides act is to modulate specific components of the homeostatic system dealing with individual nutrients and their “appetites.” This model or hypothesis can be called the peptide-specific arousal model of eating.

ffferenf Conlrols The efferent controls include the motor activities involved in identifying, obtaining, and ingesting food as well as the efferent effects on nutrient partitioning produced by the autonomic nervous system and several circulating hormones. Electrical stimulation of the lateral hypothalamus initiates a complex sequence of motor activities that leads to the initiation of food seeking, the identification of food, and the killing and ingestion of food. Further discussion of this system is beyond the scope of this review. Autonomic nervous system and nutrient partitioning. Both the sympathetic and parasympathetic nervous systems may be involved in the development of obesity.12In animals where obesity follows hypothalamic lesions there is evidence for increased activity of the efferent parasympathetic nervous system (vagus nerve). Vagal stimulation helps to increase the insulin secretion that characterizes this syndrome.12 Reduction in sympathetic activity is also characteristic of the obese state and may enhance insulin secretion and nutrient partitioning. In the experimental animal there is an inverse relationstup between the activity of the sympathetic nervous system

and food intake.16 In spontaneously feeding rats there is a negative correlation throughout the 24 hours between basal activity of the sympathetic nervous system and spontaneous food intake. In addition, almost all experimental maneuvers we have tested that increase food intake, such as lesions in the ventromedial hypothalamus or genetic obesity, decrease the activity of the sympathetic nervous system. Conversely, those maneuvers that decrease food intake, such as lateral hypothalamic lesions or injections of the appetite-suppressant drug fenfluramine, increase sympathetic activity.12 This relationship between food intake and the efferent sympathetic nervous system can be integrated with the earlier discussion of hypothalamic monoamines in the following diagram in Figure 5. Food intake is initiated centrally. In anticipation of food intake, vagal activity rises with an increase in cephalic-phase insulin release from the pancreas. As food enters the stomach and intestine it signals an increase in peripheral efferent sympathetic activity, which activates p-3-adrenergic receptors and their thermogenic responses.17 Beta-3 receptors can also mediate satiety.18 This effect of the sympathetic nervous system may be part of an efferent homeostatic feeding system. It is proposed that in animals and humans, ingestion of a meal enhances sympathetic efferent output. This increased sympathetic activity initiated by food intake might in turn serve as an inhibitor of feeding and act as part of the satiety system. Sympathetic activity might also be involved in partitioning nutrients between fat and protein. Treating pigs, cattle, and sheep with drugs that act on p-adrenergic receptors increases protein storage and decreases fat storage without changing food intake. This implies an important role for these receptors in the storage of body nutrients (Figure 3).19 Efferent hormonal mechanisms and nutrient partitioning 1. Insulin: Increased levels of insulin are characteristic of obesity. Injections of insu-

lin can increase food intake and produce obesity, probably by lowering glucose concentrations. Injection of 2-deoxy-D-glucose, an analogue of glucose, stimulates food intake by inhibiting intracellular glucose metabolism. Insulin has been proposed as a signal to the brain about the quantity of peripheral fat stores. One major problem with this hypothesis is that insulin levels fall rapidly following caloric restriction and long before there are significant changes in the quantity of body fat. Moreover, some experimental types of obesity occur with little or no rise in the concentration of insulin. There are two other interpretations of the hyperinsulinemia of obesity: First, the rise in insulin may be a reflection of high levels of nutrient intake. Since insulin is essential for storage of nutrients as fat, increased flux of nutrients would be expected to increase insulin. Second, hyperinsulinemia may reflect actual or apparent hypothalamic resistance to insulin action. In this case increased insulin secretion would be modulated by changes in the function of the autonomic nervous system resulting from resistance to the action of insulin in the central nervous system. 2. Adrenal steroids: The development or progression of experimental obesity is either reversed or attenuated by adrenalectomy.’* In clinical medicine Addison’s disease, with adrenal insufficiency, is associated with leanness whereas Cushing’s syndrome, which has high levels of adrenal steroid secretion, is associated with obesity. Because almost all defects in genetically obese animals are reversed by adrenalectomy and because clinical changes in adrenal status can produce leanness or obesity, glucocorticoids might play a key role in the development and maintenance of the obese state. Corticosteroids are thus involved in the partitioning of nutrients between fat and protein. Dehydroepiandrosterone has been shown to reduce fat accretion in several speciesm One mechanism by which it could work is through inhibition of corticosteroid or mineralocorticoid interaction with their receptors. Obesity appears to be a failure in the hoNUTRITKlN RWIEWSIVOL 49, NO 2IFEBRUARY 1991 39

meostatic model for nutrient balance (Figure 5). It appears to be a failure of nutrients to stimulate the sympathetic nervous system that requires permissive levels of adrenal glucocorticoids. Stimulation might fail because afferent signals are not generated effectively; the receptors for these signals in the central nervous system do not respond adequately or the signals are not transduced into effective efferent messages. 3. Growth hormone is involved in calorigenesis and nutrient partitioning. In obese humans the concentrations of circulating growth hormone are low and its release in response to most, if not all stimuli, is blunted. Yet growth hormone increases the metabolic rate of both lean and obese subjects.21It also increases protein deposition and reduces fat. In animals growth hor-

AFFERENTS

CONTROLLER

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EFFERENTS

Neural

CONTROLLED SYSTEM

Figure 5. A detailed model of the control of food intake. Details of the nutrient balance approach have been presented, with particular emphasis on the controller. 40 NUlRffION REVIEWSIVOL 49, NO ZIFEBRUARY 1991

mone will increase milk production and the percentage of food intake that is deposited as protein. Consideration of Treatments for Obesity Using the Nutrient Balance Model An approach to treating obesity can be conceptualized using the nutrient balance model described earlier. A list of potential treatments generated from the model this way is summarized in Table 1.

Controlled System Gastrointestinal tract. There are several ways in which modulation of ingestion, digestion, and absorption of food might be used to treat obesity. First, the nutrient density or units of food energy per unit of food weight might be reduced. This concept would suggest the use of bulking agents and high-fiber diets, or diets high in complex carbohydrates and low in fat. Alternatively, palatability and caloric content can be dissociated. Saccharin and aspartame are two sweeteners with much lower caloric value than carbohydrate. The key question is how much “caloric compensation” will occur if these sweeteners are used. Most studies22suggest that compensation is nearly complete. Simplessem is a processed protein whose taste characteristics as a table spread and in frozen desserts are like fat, yet it has the caloric value of protein, i.e., 4 kcal/g as opposed to 9 kcal/g for fat. It is not yet known whether caloric compensation occurs in diets containing Simplessem. Second, the digestion of nutrients might be altered. Two approaches have been developed. The first involves disruption of fat digestion and absorption and the second involves disturbing carbohydrate digestion. Tetrahydrolipstatin is a drug that inhibits pancreatic lipase and thus reduces hydrolysis of exogenous triglyceride. In experimental tests this agent is effective in reducing fat absorption and slows weight gain. L

Simplessem (Nutras weet).

TABLE 1 A Nutrient Balance Approach to Treatment of Obesity Commnent Controlled system

Mechanism

Example

High carbohydrate-low-fat diet Fiber Simplessea Sucrose polyester Tetrahydrolipstatin Sucrose polyester Disaccharidase inhibitors Cholest yramine Cold exposure Exercise Prazosin Thyroid hormone Growth hormone Beta-3 adrenergic agonists Ephedrine Caffeine Beta-3 adrenergic agonists Growth hormone Corticosteroids Androgens Estrogens

Decrease nutrient density of food

Reduce digestibility

Disrupt micelle formation Increase energy expenditure Exercise Vasodilation Calorigenic drugs

Change nutrient partitioning

Afferent signals

Saccharin Aspartame Benzocainc Capsaicin Gastric balloon Aconitase Cholecystokinin Prwolipase signal peptide Bombesin 3-hydroxybut yrate Lactate I -butene-4-olide 3.4-dihydroxybutyrate

Palatability Sweeteners Topical anesthetic Taste-altering drugs Gastric distension GI peptides

Nutrients

Controller

Picrotoxin

GABAergic antagonist (GABA-A receptors) Adrenergic agonists (alpha-], beta-3) Scrotonergic agonists

Phenethylamine derivatives Fenfluramine Fluoxetine Sertraline

Histaminergic (H- I ) agonists Peptides

Efferent mechanisms

Thermogenic drugs Jaw-wiring Steroid removal Inhibit prolactin release

Cholecystokinin agonists Opioid antagonists (naloxone; nalfemene; kappareceptor antagonists) NPY antagonists CRH agonists Beta-3 agonists &

Adrenalectomy RU-486 blockade of steroid receptors Dopamine agonists

treating obesity. Neuropeptide Y stimulates feeding and increases carbohydrate intake. Chronic administration of neuropeptide Y produces obesity. Therefore, antagonists to this peptide might effectively treat obesity. Finally, CRH inhibits food intake.12a2’ Agonists to its receptors might be useful against specific types of eating disorders.

5. Peikin SR. Role of cholecystokinin in the control

€fierent Mechanisms Food intake can be reduced by a variety of surgical procedures, including jaw wiring, all of which reduce the entry of food into the GI tract. Beta-3 agonists act on brown adipose tissue and other sites to increase heat production. They also decrease food intake and modify nutrient partitioning. Thus, either through their thermogenic effects or their action on p-3 receptors, p-3 agonists might be useful.

8.

6.

7.

9.

10.

11.

Summary At present, only a few drugs are marketed for treatment of obesity. The recent explosion of knowledge about mechanisms involved in obesity offers great promise for the development of newer approaches to this chronic problem. A number of mechanisms control body fat and nutrient partitioning. Their multiplicity suggests that several new approaches to treatment will be developed and that the use of complementary drugs might provide the best treatment. This approach would be analogous to the current pharmacologic treatment of hypertension. 1. Bray GA. Obesity-a disease of nutrient or energy balance. Nutr Rev 1987;45:33-43 2. Flatt JP. Dietary fat, carbohydrate balance, and weight maintenance: effects of exercise. Am J Clin Nutr 1987;45:296-306 3. Ravussin E, Lillioja S,Anderson TE. Christin L. Bogardus C. Determinants of 24-hour energy expenditure in man: methods and results using a respiratory chamber. J Clin Invest 1986;78:156878 4. Bogardus C, Lillioja S,Ravussin E. Abbot W, Zawadzki TK, Young A. Familial dependence of the resting metabolic rate. N Engl J Med 1986;315: 96-100 44

12.

13.

14. 15.

16.

17.

18.

19.

of food intake. Gastroenterol Clin North Am 1989;18:757-75 Dourish CT. Rycroft W, lversen SD. Postponement of satiety by blockade of brain cholecystokinin (CCK-8) receptors. Science 1989;245: 1509- 11 Gibbs J. Fauser DJ, Rowe EA, Rolls BJ, Rolls ET, Madison SP. Bombesin suppresses feeding in rats. Nature 1979;282:208-10 Shargill N, Bray GA. Erlansen-Albertsson C. Procolipase pentapeptide (VPDPR) suppresses food intake following injection into the third ventricle. Int J Obes 1989;13:578(abstract) Hauger R. Hulihan-Giblin 8, Angel I. et al. Glucose regulates (W) ( +)-amphetamine binding and Na + K + ATPase activity in the hypothalamus: a proposed mechanism for the glucostatic control of feeding and satiety. Brain Res Bull 1986a;16:281-8 Scharrer E, Langhans W. Control of food intake by fatty acid oxidation. Am J Physiol 1986;250: R1003-6 Astrup A, Toubro S. Cannon S.Hein P, Breum L, Madsen J. Caffeine: a double-blind, placebocontrolled study of its thermogenic, metabolic, and cardiovascular effects in healthy volunt e e r ~ . Am ~ - ~J Clin Nutr 1990;51:759-67 Bray GA. York DA, Fisler JS. Experimental obesity: a homeostatic failure due to defective nutrient stimulation of the sympathetic nervous system. Vitam Horm 1989;45:1-125 Sakata T, Ookuma K, Fukagawa K, et al. Blockade of the histamine H,-receptor in the rat ventromedial hypothalamus and feeding elicitation. Brain Res 1988;441:403-7 Morley JE. Neuropeptide regulation of appetite and weight. Endocr Rev 1987;8:256-87 Arase K, Fisler JS, Shargill NS, York DA, Bray GA. lntracerebroventricular infusions of 3-OH08 and insulin in a rat model of dietary obesity. Am J Physiol 1988;255:R974-81 Sakaguchi T. Takahashi M, Bray GA. Diurnal changes in sympathetic activity: relation to food intake and to insulin injected into the ventromedial or suprachiasmatic nucleus. J Clin Invest 1988;82:282-6 Emorine L, Marullo S,Briend-Sutren MM. et al. Molecular characterization of the human beta-3adrenergic receptor. Science 1989;245:118-21 Tsujii S. Bray G. Food intake responses to BRL-37344 and clonidine in genetically obese rats. FASEB J 1989;3:A377 Yen T, Anderson D. Veenhuizen E. Phenethanolamines: reduction of faC and increase of muscle, from mice to pigs. In: Lardy H. Stratman F, eds.

20.

21.

22. 23.

24.

Hormones, thermogenesis, and obesity. New York: Elsevier, 1989;455-64 Cleaty M. Antiobesity effect of dehydroepiandrosterone in the Zucker Rat. In: Lardy H, Stratman F, eds. Hormones, thermogenesis. and obesity. New York: Elsevier. 1989:365-76 Bray G. Calorigenic effect of human growth hormone in obesity. J Clin Endocrinol Metab 1969; 29:119-22 Bray GA, Gray DS. Treatment of obesity: an overview. Diabetes Metab Rev 1988;4(7):653-79 Sheldahl LM, Buskirk ER, Loomis JL. Hodgson JL, Mandez J. Effects of exercise in cool water on body weight loss. Int J Obes 1982:6:29-42 Bray GA. Raben MS. London0 J, Gallagher TF. Jr. Effects of triiodothyronine, growth hormone and

anabolic steroids on nitrogen excretion and oxygen consumption of obese patients. J Clin Endocrinol Metab 1971 ;33:293-300 25. Arch J. Bywater R. Coney K. Ellis R. Thrulby P. Influences on body composition and mechanism of action of the p-adrenoceptor agonist BRL26830A. In: Lardy H. Stratman F, eds. Hormones, thermogenesis. and obesity. New York: Elsevier, 1989;465-76 26. Okada S, Bray GA. York DA. Blockade of glucocorticoid receptors with RU-486 prevents dietary obesity. FASEB J 1990;4:A918 27. Leibowitz S. Brain monoamines and peptides: role in the control of eating behavior. Fed Proc 1986;45:1396-403

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