Metabolic and Hormonal Controls of Food Intake: Highlights of the Last 25 Years—1972–1997

Appetite, 1997, 29, 135–152

Metabolic and Hormonal Controls of Food Intake: Highlights of the Last 25 Years—1972–1997

L. ARTHUR CAMPFIELD Department of Metabolic Diseases, Hoffmann-La Roche Inc., Nutley, NJ 07110, U.S.A.

The six major research advances in metabolic and hormonal controls of food intake that have altered the direction or have broadened the scope of the field in the last 25 years are discussed. The advances selected are: (1) GI processes and meal termination—the CCK pathway; (2) Brain insulin hypothesis; (3) Glucosedependent processes in periphery, plasma, and brain including the transient declines in blood glucose signaling meal initiation; (4) Fatty acid oxidation in the liver; (5) Behavioral and metabolic patterns; and (6) New pathways from molecular genetics and molecular biology—the OB protein pathway.  1997 Academic Press Limited

O: A   M C  F I D  P 25 Y Looking back over the last 25 years of research in the area of metabolic controls of food intake, reveals a rich history and a succession of numerous major advances. Many of these advances and much of the research in this field have been presented, discussed, or reviewed at the Columbia University Seminar on Appetitive Behavior. Thus, it is fitting to review these accomplishments and to select the top six advances over the last 25 years on the occasion of the 25th Anniversary of the Columbia University Seminar on Appetitive Behavior. The criteria used to select the major advances in the metabolic controls of food intake is ultimately subjective. However, an attempt was made to identify research advances in the field that have altered the direction or have broadened the scope of the field. Metabolic controls were interpreted to include metabolic and hormonal factors that modify food intake. Included are the advances upon which the current status of the field of metabolic controls of food intake is based. As is the case in most scientific fields, it is often difficult to determine where rapid advances in an important subfield begin and where they end. With this consideration of the fallibility Based on a presentation to the 25th Anniversary Symposium of the Columbia University Seminar on Appetitive Behavior, March 6, 1997 (Harry R. Kissileff, Chairman). Supported in part by HoffmannLa Roche Inc., McNeil Speciality Co., Miles Inc/BayerAG and The New York Obesity Research Center, St Luke’s/Roosevelt Hospital. Address correspondence to: Dr L. A. Campfield. 0195–6663/97/100135+18 $25.00/0/ap970122

 1997 Academic Press Limited

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T 1 Important advances during the past 25 years Russek’s hypothesis–liver metabolism, glycogen. Novin’s work on peripheral hexose infusions. Booth’s work on conditioned feeding-glucose. Experimental data favors rejection of Mayer’s glucostatic hypothesis. Japanese school of neurophysiology—peripheral and central glucose-sensitive neurons. Neurophysiology of taste in primates—alterations by glucose. Glucose modulates sensation. Caloric metering of loads by monkeys. GI processes and meal termination—CCK pathway. Glucoprivation and lipoprivation studies. Dual periodicity and integrative concepts of Le Magnen. Brain insulin system. Transient declines in blood glucose-causal signal for meal initiation and revision of Mayer’s glucostatic hypothesis. Liver fatty acid oxidation hypothesis and experimental support. Amino acids as signals. Metabolism de fond. Metabolic patterns as signals for organizing food intake behavior. Integrative controls combining carbohydrate, fatty acid, and amino acid-based signals. Laboratory studies of human feeding—studies in subjects with obesity and eating disorders. Fat plus/minus studies in humans. Impact of molecular biology and molecular genetics. Neuropeptides-NPY, CRF, enterostatin, opiods. OB protein pathway.

inherent in such a selection, my list of the major advances in the metabolic and hormonal controls of food intake is shown in Table 1. The list begins with Russek’s seminal hypothesis concerning liver metabolism and glycogen and their effects on food intake (Russek, 1963), continues with Novin’s work on the effects of peripheral glucose infusions and his thoughtful approach and analysis of the important role of metabolic signals and the liver in the control of food intake (Novin, 1976). Together with Booth’s early work on conditioned feeding with glucose (Booth, 1978), these studies demonstrated an important role for hexoses in the control of food intake. However when the Seminar began in 1972, experimental evidence did not support Mayer’s glucostatic hypothesis (Campfield & Smith, 1990a; Campfield & Smith, 1997; Mayer, 1953; 1955; Smith, Gibbs, Strohmayer & Stukes, 1972). The field had rejected the dominant idea that had been driving much of the experimental work and was searching for new paradigms to explain the regulation of food intake in animals and people. Neurophysiological studies of feeding and taste have provided an important integrative component to the field. The work of Oomura, Niijima, Ono and Karadi, which I have combined together as the Japanese School of neurophysiology of feeding, has been very influential (Karadi, Faludi, Hernadi & Lenard, 1995; Niijima, 1983; Ono et al., 1982; Oomura, 1983; Oomura, Shimizu, Miyahara & Hattori, 1982). I think that the identification of central and peripheral glucose-sensitive neurons by these investigators and their colleagues was a major milestone in our field. The studies of the neurophysiology of taste by Scott, Rolls and Norgren (Norgren, 1976; Norgren, 1983; Rolls, Scott, Sienkiewicz & Yaxley, 1988; Scott,

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Yaxley, Sienkiewicz & Rolls, 1986) have given us important evidence that metabolic fields can condition and modulate taste perception. The next set of advances brought the field into intimate and sustained contact with the gastrointestinal tract. The caloric metering hypothesis of McHugh and Moran (McHugh, Moran & Wirth, 1982) and the CCK hypothesis for meal termination, based on the work of Gibbs, Smith, Moran, McHugh and others, have provided major contributions to gastrointestinal processing and meal termination (Gibbs, Young & Smith, 1973; Moran & McHugh, 1982; Smith & Gibbs, 1994). The very influential target article of Le Magnen on the metabolic basis of the dual periodicity of feeding provided a synthesis of the regulation of food intake and body energy storage (Le Magnen, 1980). Le Magnen has provided an evolving synthesis of integrative controls and other unifying concepts of the field of ingestive behavior and the regulation of body energy storage. This synthesis has been presented in a series of review articles and monographs during the ‘‘lifetime’’ of the Columbia Seminar (Le Magnen, 1985; 1992). The studies with 2-deoxy--glucose (2-DG) and other metabolic inhibitors of Ritter (Ritter & Hutton, 1995) and others have provided important information on the effects of glucose and lipids in the control of food intake. Additional evidence also emerged supporting a role for amino acids in the control of food intake (Gietzen, 1993). The next major advance was the studies that established the transient decline in blood glucose as a signal for meal initiation (Campfield & Smith, 1990a; 1990b). The set of studies that have identified fatty acid oxidation as an important signal in the metabolic control of food intake also significantly advanced the field (Friedman, 1990a; 1990b; Friedman & Tordoff, 1986; Friedman, Tordoff & Ramirez, 1986). The meal-associated changes in metabolism de fond of Nicolaidis (Nicolaidis & Even, 1984) provided evidence that changes in energy expenditure can also modify feeding behavior. Additional experimental support for the concept of integrated controls of food intake that combine carbohydrate, fatty acid and amino acid based signals was also obtained as a result of many groups of investigators. Taken together, the results of these metabolic studies lead to the concept of metabolic patterns as signals for organizing feeding behavior (Campfield & Smith, 1990a). The ability to study human eating behavior in the clinic, laboratory and in ‘‘reallife’’ settings significantly advanced in the last 25 years. This important research area has moved from purely observational studies in very artificial settings to intervention studies using pre-loads and modified food items in more natural situations (Campfield, 1996). One example was the augmentation or reduction of the dietary fat in test foods presented to humans with normal and altered feeding behavior and the subsequent food intake was measured. The last three advances relate to the positive impact that progress in neurobiology, the identification of neuropeptides, and the applications of molecular biology and molecular genetics have had on our understanding of the metabolic and hormonal controls of food intake (Campfield, Smith & Burn, 1996; 1997). Many of these research findings were first presented, discussed, or reviewed at several important conferences and appeared in a series of publications in addition to presentations at the Columbia University Seminar on Appetitive Behavior. Some of these conferences and publications in the field of metabolic and hormonal controls of food intake are listed in Table 2. This list, like that of the major advances, is from my personnel perspective and not comprehensive, and certainly some important conferences and publications are omitted.

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T 2 Important conferences and publications UCLA conference and ‘‘Hunger’’ book—1976 (Novin, Wyrwicka, & Bray, 1976). Los Angeles conference and ‘‘Blue’’ Book—1982 (Hoebel & Novin, 1982). UCLA-Japan Conferences and San Antonio and Napa conferences—Brain Research Bulletin Supplements (Brain Research Bulletin 14,1985). Kroc Foundation conference on the Vagus Nerve—1983 (J. Autonomic Nervous System 9, 1983). Franklin-La Fayette Sympagium in La Napoule, France. International Commission for the Physiology of Foods and FIuid Conferences. Handbook of Behavioral Neurobiology—Neurobiology of Food and Fluid Intake—1990 (Stricker, 1990). SSIB Independent Meetings. FASEB Summer Conference on the Regulation of Energy Balance, Copper Mountain—1995. Society for Neuroscience Symposium on the Neurobiology of OB protein—1996.

T 3 Metabolic and hormonal controls of food intake—six major advances (1972–1997) GI processes and meal termination—the CCK pathway. Brain insulin hypothesis—(including neuropeptides NPY and CRH). Glucose-dependent processes in periphery, plasma, and brain—Transient declines in blood glucose signaling meal initiation. Fatty acid oxidation in the liver. Behavioral and metabolic patterns. New pathways from molecular genetics and molecular biology—the OB protein pathway.

M  H C  F I—S M A (1972–1997) The identification of the six major research advances in the field of metabolic controls of food intake was accomplished by grouping closely related major advances listed in Table 1 under a suitable, inclusive label and rank ordering the resulting topics. The six major advances are listed in Table 3. Gastrointestinal Processes—The CCK Hypothesis The central role of the cholecystokinin (CCK) hypothesis in the study of ingestive behavior is widely acknowledged and the details of the hypothesis and its experimental support are widely known (Gibbs et al., 1973; Smith & Gibbs, 1994). The control of gastric emptying has always been an important area of research. Progress in this field has provided a much better understanding of this process than we had 25 years ago. The caloric metering hypothesis of Moran and McHugh (McHugh et al., 1982; Moran & McHugh, 1982), which was based on studies of gastric emptying in monkeys, caused some deep reflection on just what was being measured in the regulation of gastric emptying. The identification of chemoreceptors and mechanoreceptors in the intestinal wall and the neural afferents that relay that in-

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F 1. Duration of action of CCK-8. CCK-8 was injected IP in rats at the time indicated before a meal. Rats were trained to eat two meals each day. Each meal was one hour long and the two meals were separated by one hour. Ε, 1st meal; ∧, 2nd meal.

formation to the brain was a very important step. The next advance was a major contribution to gastrointestinal processing and meal termination—the CCK hypothesis based on the work of Smith, Gibbs, Moran, McHugh, Kissileff and others (Gibbs et al., 1973; McHugh et al., 1982; Moran & McHugh, 1982; Moran, Robinson, Goldrich & McHugh, 1986). The CCK hypothesis postulated that food in the intestine causes the release of CCK which acts on CCK-A receptors in the vagus nerve to provide sensory information to the brain that causes meal termination. The critical pieces in that hypothesis were identification of the dependence on the vagus nerve, the identification of the CCK-A (peripheral) and CCK-B (central) receptors, and the demonstration that CCK-A antagonists increased food intake (Moran et al., 1986). Figure 1 shows one experimental determination of the duration of action of CCK-8 in rats. Smith, Gibbs and colleagues at the Bourne laboratory of Cornell University have provided encouragement to other scientists to study CCK, generated strong experimental support for the hypothesis and written informed and scholarly summaries of the hypothesis (Smith & Gibbs, 1994). Brain Insulin Hypothesis The second major advance in the field has been the elucidation of the brain insulin system by Woods, Porte, Jr. and their colleagues in Seattle over the past 25 years (Ikeda et al., 1986; Schwartz, Figlewicz, Baskin, Woods & Porte, 1994; Schwartz et al., 1991). Figure 2 shows a schematic representation of the brain insulin hypothesis. They made the very important observation that fasting plasma insulin was proportional to adiposity or the adipose tissue mass (Kaiyala, Woods & Schwartz, 1995; Schwartz et al., 1994; 1991). A schematic diagram of this relationship is shown in Fig. 3. Based on this observation, they performed the critical experiments to show that central injections of small amounts of insulin into the cerebrospinal fluid (CSF)

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+

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F 2. Schematic representation of the brain insulin hypothesis. [Reprinted from (Kaiyala et al., 1995)].

Functional insulin

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F 3. Schematic of the relationship between fasting plasma insulin and body weight. [Reprinted from (Kaiyala et al., 1995)].

were followed by suppressed food intake and reduced body weight. These experiments were performed in a variety of species including rats, birds and monkeys. One example is shown in Fig. 4. I feel that this hypothesis was seminal for the following reasons. First, it was advanced very early; second, a sequence of very ambitious, complex studies were performed to rigorously test this hypothesis and these results provided strong

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F 4. Effect of insulin infused into the third ventricle on body weight and food intake of the heterozygous lean (Fa/fa) Zucker rat. Saline (Β, N=6) or insulin 2 mU/day (Χ, N=7) was infused for 14 days as indicated in the figure. [Reprinted from (Ikeda et al., 1986)].

experimental support; third, these studies clearly demonstrated that a peripheral circulating signal proportional to adiposity could act on brain mechanisms to alter feeding behavior and body energy balance. The idea that a large circulating protein like insulin provides important information to the brain, that insulin would act differently in the brain than in the periphery, that insulin in the brain could potentiate the effects of neuropeptides such as neuropeptide Y (NPY) and CCK, and that circulating steroids interact with the brain insulin in important ways provided the basis for the paradigm of central/peripheral integration in the regulation of food intake and body energy balance. Together with blood glucose dynamics (see below) and the CCK hypothesis, the brain insulin system provide, in my opinion, the three best examples of the periphery informing the central nervous system to control food intake. The group in Seattle has been persistent in continuing to provide experimental support for the hypothesis and for providing at regular intervals informed, careful, well written and scholarly summaries of the hypothesis. The brain insulin hypothesis has also provided strong evidence for the involvement of brain neuropeptides, in addition to monoamine neurotransmitters, in the control of food intake. The Seattle group demonstrated that central administration of insulin decreased the expression of NPY m RNA in the arcuate nucleus of the hypothalamus. In addition, they also showed that the central administration of insulin increased the expression of corticotropin releasing hormone (CRH) mRNA in the paraventricular nucleus of the hypothalamus (Kaiyala et al., 1995; Schwartz et al., 1994; 1991). Thus, central administration of insulin altered the gene expression of two major neuropeptides (decreased NPY and increased CRH mRNAs) that are important regulators of food intake and body energy regulation as well as other biological processes. A final reason that the brain insulin system had an important impact on our field was that the experimental paradigm developed over many years to study the

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brain insulin system was used by our group and many other investigators to rapidly elucidate the OB protein pathway following the cloning of the ob gene (see below). Glucose-dependent Processes in The Periphery, Plasma, and Brain—The Transient Decline in Blood Glucose The next major advance in the understanding of the metabolic and hormonal controls of food intake was the elucidation of the important role of glucose-dependent processes in the periphery, plasma and brain. This is an area in which my laboratory lead by Franc¸oise Smith have worked and, as a result, we have had the chance to observe the development of this area first-hand. Throughout the history of the area of metabolic control of food intake, attention has often been focussed on the changes in blood glucose as a potential regulatory signal. The early ideas of Carlson (Carlson, 1916) and the development of the glucostatic theory of Mayer (Mayer, 1953; 1955) played a major role in the development of the metabolic control of food intake and the entire field of ingestive behavior. The development and transformation of these ideas during the past 25 years has resulted in the best established metabolic control of food intake, the transient decline in blood glucose. We know that glucose-dependent processes that are important in the regulation of metabolism occur in many peripheral organs, tissues and cells. Glucose circulates in the blood and, based on the work of Oomura, Niijima and other investigators (Niijima, 1983; Ono et al., 1982; Oomura, 1983; Oomura et al., 1982), we know that several brain areas receive direct and/or synaptic inputs relating to the dynamic changes in blood glucose concentrations on a continuing basis through a whole set of peripheral and central receptors: on, off, rate-sensitive, rapidly adapting, and slowly adapting (Campfield & Smith, 1997). These receptors provide a rich and complete representation of the dynamics and patterns of blood glucose to the brain throughout the day (Campfield & Smith, 1990a). The rebirth and further evolution of the role of blood glucose in the control of food intake followed the demonstration in 1980 by Louis-Sylvestre in Le Magnen laboratory at the College de France that a small decline in blood glucose occurred prior to meal initiation in free-feeding rats (Louis-Sylvestre & Le Magnen, 1980). This work built directly on the important work of Strubbe and Steffens who developed the necessary techniques for frequent blood withdrawal for glucose and insulin in undisturbed rats before, during and after meals. Although the discrete sampling techniques utilized by Strubbe and Steffens (Steffens, 1969) prevented them from detecting the decline in blood glucose, they correctly determined that plasma insulin reaches its lowest point just before meal initiation (Strubbe, Steffens & De Ruiter, 1977). The observation of transient declines in blood glucose and the establishment of it as a signal for meal initiation was the direct result of a combination of the application of a technological innovation (continuous recording of blood glucose) and the idea that important information could be embedded in patterns. The observation of a small fall in blood glucose prior to meal initiation was controversial, and widely discussed (Campfield & Smith, 1990a; 1997). Following a sabbatical visit in Le Magnen’s laboratory, we confirmed the presence of a small change in blood glucose prior to meal initiation in free-feeding rats, a phenomenon we named the ‘‘transient decline in blood glucose’’ (Campfield & Smith, 1990a). In addition, we collected evidence that the transient decline was an internally

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F 5. Pattern of blood glucose concentration and behavior in an obese Zucker (fa/ fa) rat. Note that each fall in blood glucose is associated with meal initiation, even if it occurred when the rat was sleeping. In contrast, the rat stops eating and returns to sleep or other behavior when glucose rises toward baseline. [reprinted from (Campfield & Smith, 1997)].

mediated, spontaneous event that was causally related to the onset of feeding (meal initiation) but not the size or duration of the meal (Campfield & Smith, 1990a; 1990b). We also presented evidence that the meals in genetically and experimentally obese and experimentally induced diabetes rats were preceded by transient declines in blood glucose that were qualitatively similar to those observed in lean rats (Campfield & Smith, 1990a). Figure 5 shows the pattern of blood glucose and behavior in an obese Zucker (fa/fa) rat. Each fall in blood glucose is associated with meal initiation, even if it occurred when the rat was sleeping. In contrast, the rat stops eating and returns to sleep or other behavior when glucose rises toward baseline. The mean change in blood glucose concentration as a function of time in rats is shown in Fig. 6. Here we can see that the transient decline in blood glucose is brief, small, symmetrical and that meal initiation usually began as the glucose concentration was rising toward baseline (Campfield & Smith, 1990a; 1990b). Working together with Rosenbaum and Hirsch, of Rockefeller University, we were able to detect a similar transient decline in blood glucose prior to changes in hunger or meal requests in human subjects in the post-absorptive state and isolated from temporal cues. Examples of the temporal evolution of blood glucose concentration prior to meal requests in shown in Fig. 7. In these studies, we found a significant association between transient declines in blood glucose and meal requests (Campfield, Smith, Rosenbaum & Hirsch, 1996). The patterns of change, or the dynamics, of blood glucose concentration throughout the day and the recognition of these patterns in the brain, together with the well-described pathways by which 2-DG causes an emergency feeding response, provide an adequate metabolic signal to explain meal initiation. Thus, the identification of a glucose-dependent process, the transient decline in blood glucose, that signals a complex behavior like meal initiation was an important achievement of the

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F 6. The mean change in blood glucose concentration as a function of time in rats. Note that the transient decline in blood glucose is brief, small, symmetrical and that meal initiation usually began as the glucose concentration was rising toward baseline. [Reprinted from (Campfield & Smith, 1990a)].

past 25 years in our field (Campfield & Smith, 1997; Campfield et al., 1996). The identification of this system now allows us to ‘‘ride along with the glucose molecule on the information pathway’’ from the periphery, into the blood, into brain and back to the periphery again as information embedded in the patterns of blood glucose concentration is used to signal meal initiation (Campfield & Smith, 1990a; Campfield & Smith, 1997). It is my hope that this pathway will serve as a useful example in the elucidation of the pathways by which other metabolic and hormonal signals regulate feeding behavior. Fatty Acid Oxidation in the Liver The next major advance in our understanding of metabolic and hormonal control of food intake has been the demonstration that the liver is ideally suited and situated to integrate the flux of carbohydrate, fat and protein metabolism and provide a signal that can be used to organize feeding behavior. The metabolic flux of glucose and the oxidation of fatty acids within the liver generates ATP and the amount or availability of ATP or a specific profile of phosphate moieties within the liver produces a signal that is used to control feeding behavior. The work of Friedman, Tordoff, Langhans, Scharrer and others (Friedman, 1990a; 1990b; Friedman & Tordoff, 1986; Friedman et al., 1986; Langhans & Scharrer, 1987) in the field have provided clear evidence, building on Russek’s hypothesis, that experimental alterations that are made in liver metabolism by drugs result in predictable changes in food intake. Thus, fatty acid oxidation provides an integrated signal that reflects integrated metabolic state and this signal acts over a time period longer than a single meal. This integrated signal is then used by the brain to regulate food intake.

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F 7. Examples of the temporal evolution of blood glucose concentration prior to meal requests. Healthy subjects are in the post-absorptive state and are isolated from time cues. [Reprinted from (Campfield et al., 1996)].

Since liver fatty acid oxidation is also sensitive to changes in blood glucose, the resulting liver-generated signal will also be dependent on blood glucose. It is also possible that the signal related to fatty acid oxidation interacts with the transient decline in blood glucose signal within the brain.

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These investigators have taken a very beautiful and appealing hypothesis, advanced by Booth (Booth, 1978) and Nicolaidis (Nicolaidis, 1974), with little direct support 25 years ago and have provided several lines of converging evidence that has convincingly demonstrated an important integrative metabolic signal controlling food intake. The use of NMR by Friedman’s laboratory to quantify the phosphate profile within the liver as fatty acid oxidation was experimentally manipulated is an excellent example of the application of new technology to the study of the metabolic and hormonal controls of food intake (Rawson, Blum, Osbakken & Friedman, 1994). Behavioral and Metabolic Patterns An advancement of a more general nature has been the elaboration of behavioral and metabolic patterns and demonstration of their important role in the metabolic and hormonal control of food intake. At one level or another, most of the members in our field are ‘‘behavioral scientists’’ in the sense that we are fascinated by the ingestive behavior of animals. We desire to know ‘‘why animals do what they do?’’ and ‘‘why do they make certain food choices?’’ However, we are also ‘‘metabolic scientists’’ in the sense that we are very interested in the answer to the following major question in our field that has been repeatedly advanced and discussed by Le Magnen (Le Magnen, 1980; 1992) and others ‘‘How do animals match continuous body energy demands with discrete feeding bouts?’’ Behavioral patterns Meal pattern analysis has been the foundation of the field of metabolic and hormonal controls of feeding. It was an important component of the work of Richter, Le Magnen, Blundell, Kissileff, ourselves, and others (Blundell, 1991; Kissileff, Nakashima & Stunkard, 1979; Le Magnen, 1980; 1992; Richter, 1942–43). Meal pattern analysis has been the anchor of the attempt to match observed feeding behavior with metabolic and hormonal variables in the physiology of feeding. The meal pattern defined the relevant time domains of feeding behavior, clearly separated the processes of meal initiation, maintenance and meal termination, and defined the intermeal interval. This analysis defined the time domains and, often, provided insights into the possible anatomical locations in which to look for metabolic and hormonal mechanism that may play a role in feeding (Le Magnen, 1980; 1985; 1992). The satiety sequence, the ordered events that animals go through when they voluntary terminate meals, has been extremely important (Antin, Gibbs, Holt, Young & Smith, 1975). Since many of the experiments conducted in the last 25 years have been directed at the study of satiation, it has been important to determine if the experimentally induced suppression of feeding observed was similar to spontaneous meal termination or not. The taste reactivity test developed by Grill and Norgren (Grill & Norgren, 1978) allows the determination of the acceptance or rejection of tastants in rats. The ability of the taste reactivity test to finely analyse multiple behavioral responses and characterize the ‘‘meaning’’ of these responses to the animal in terms of the tastants studied were very important contributions to our field. Since the integration of multiple ‘‘pieces’’ of specific behaviors is required to support feeding behavior, the ability of the taste reactivity test to finely analyse multiple behaviors emphasizes the need to observe multiple behaviors in individual subjects.

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The separation of feeding behavior in two aspects: ‘‘appetitive’’ and ‘‘comsummatory’’ was also an important contribution to our increased understanding of the metabolic and hormonal controls of food intake. This decomposition has been used and discussed by many investigators. Weingarten has used these concepts to distinguish behaviors that occurred before the expected delivery of food from the actual acts of eating food in his elegant studies of conditioned feeding (Weingarten, 1983; Weingarten & Martin, 1989). Another informative behavioral sequence was intraoral infusions in the pre-meal, meal, or post-meal periods in rats. This technique extended the taste reactivity test to the ingestion of liquid meals delivered into the oral cavity at the investigator’s discretion (Seeley, Kaplan & Grill, 1995). The final behavioral sequence is the sequence of behaviors leading to spontaneous meal initiation in non-deprived, free-feeding rats. Although unknown to many investigators focussing on satiation or deprivation induced feeding, this sequence has been very informative in describing and experimentally characterizing spontaneous meal initiation (Campfield & Smith, 1990a). Additional study of this sequence will be both informative and worthwhile. Metabolic patterns I support the hypothesis that metabolic patterns are detected and recognized by the central nervous system and they are used to determine the behavioral patterns that we can observe in the laboratory. The first of these is the pattern of mealstimulated plasma concentrations of glucose, insulin, and glucagon which defined the temporal sequence of the rise and fall of these important metabolic and hormonal signals (Campfield & Smith, 1990a). The description of these patterns was an important advance which allowed us to understand the metabolic response to meals. The second set include the temporal patterns in specific body compartments of CCK (intestine), insulin (periphery and brain) (Schwartz et al., 1994; 1991), temperature (core and skin) (De Vries, Strubbe, Wildering, Gorter & Prins, 1993) and wholebody patterns of lipogenesis and lipolysis (Le Magnen, 1980; 1992) and the metabolism de fond (Nicolaidis & Even, 1984). The third important metabolic pattern identified was the definition of the transient declines in blood glucose concentration, which, as described above, is a signal for meal initiation (Campfield & Smith, 1990a). Finally, patterns of fatty acid oxidation and/or ATP in liver provided important support for these parameters as important metabolic controls of food intake (Friedman, 1990a). New Pathways from Molecular Genetics and Molecular Biology—The OB Protein Pathway The sixth major advance in our field is the discovery of new pathways from molecular genetics and molecular biology as exemplified by the OB protein pathway. Research in the last two years has identified the key elements of the OB protein pathway shown in Fig. 8 including adipose tissue secretion of OB protein, binding proteins in plasma, transport system into the brain, OB-R receptors in hypothalamic nuclei, neural and neuroendocrine outputs to peripheral tissues (Campfield et al., 1996; 1997). The rapid elucidation of the OB protein pathway was accomplished by the application of the experimental paradigm developed in the study of the brain insulin system at the University of Washington.

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OB Protein secretion

Hypothalamus OB-R

ob gene

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ob gene ?

ob gene

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F 8. A schematic model of some of the important elements of the OB protein signalling pathway that regulates body energy balance. The key elements of the OB protein pathway include a transport system for OB protein to enter the brain, OB-R receptors in hypothalamic nuclei, and neural and neuroendocrine outputs to peripheral tissues. [Reprinted from (Campfield et al., 1997)]. OB

OB

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Neuronal Network

Food intake Metabolism Autonomic Nervous System Energy Expenditure

F 9. Schematic diagram of hypothetical neural networks controlling energy balance. Several ‘‘classes’’ of parallel neural pathways are represented by the four model neurons depicted. Each neuron is assumed to have the gene, synthesize and release one dominant type of neuropeptide-NPY, CRH, X, ? Each neuron has the long form of the OB-R receptor (ellipses) and the ‘‘final common pathway’’, the neuronal network controlling ingestive behavior, metabolism and energy balance, has distinct receptors for OB, NPY, CRH, X and ? OB protein is shown as circles containing ‘‘OB’’. Note that OB protein can express its biological action through five parallel paths, each mediated by a different neuropeptide-NPY, CRH, ‘‘X’’, or ‘‘?’’. The ability of OB protein to inhibit the actions of released NPY is also shown [reprinted from (Campfield et al., 1997)].

Our current working hypothesis is that OB protein is a ‘‘coordinator’’ or ‘‘organizer’’ of the seemingly disparate multiple neurotransmitter and neuropeptide effects on, and responses to, ingestive behavior and body energy balance. One representation of this hypothesis in the hypothalamus is shown in Fig. 9. Several

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‘‘classes’’ of parallel neural pathways are represented by the four model neurons depicted. Each neuron has the long form of the OB-R receptor and the ‘‘final common pathway’’ the neuronal network controlling ingestive behavior, metabolism and energy balance has distinct receptors for OB, NPY, CRH, X and ? The idea is that OB protein coordinates and integrates multiple parallel and interacting pathways and generates the appropriate behavioral and metabolic responses (Campfield et al., 1996; 1997). In summary, these are the six major advances in the field of metabolic and hormonal controls of food intake during the last 25 years. The field has moved from single observations of what is eaten, how much is eaten, and the rate of eating, to multiple, temporal observations of feeding behavior and metabolic and hormonal factors. This evolution of the field has resulted in the elucidation of the underlying physiology and increased understanding of how patterns of metabolism, including patterns of metabolites and hormones, are detected and ‘‘read-out’’ by the CNS and provide information upon which decisions are made about meal initiation, maintenance, and meal termination as well as energy expenditure and the regulation of energy balance and body fat.

T F Based on my view of the current status of the field, I expect that the field will be dominated by research in three major areas in the coming years. The first two areas are related and the second follows naturally from the first. First, I feel that the general topic of the neurobiology of ingestion and the regulation of energy balance is now at the forefront of our research agenda. Investigation of the neurobiology underlying the metabolic and hormonal controls of food intake and the regulation of energy balance will increasingly occupy our present and future students and colleagues. The focus of these studies will be the brain mechanism underlying and integrating the metabolic and hormonal controls of food intake. Progress in the neurobiology area will naturally lead to the next major area of future research: The elucidation of central/peripheral integration of signals in the control of ingestion and the identification of the molecules, mechanisms and decision rules. The understanding of how peripheral and central signals are combined and integrated and the identification of the decision rules for feeding and energy balance will, in my opinion, take the field to a new ‘‘state’’ of knowledge. We will then finally ‘‘understand’’ at the molecular level, in a deep and meaningful way, how metabolic and hormonal control signals actually lead to the feeding behavior that captures our attention and interest. This new understanding will usher in a new era in our field. The third research area will continue the investigation of the OB protein pathway and will focus on the determination of mechanisms of action of OB protein on neuropeptide pathways, gene expression and synaptic transmission with the brain. I expect that the OB protein pathway will become increasingly more important and critical to our overall understanding of the central question of our field, how information imbedded in the patterns of metabolic and hormonal variables provides signals that are used to organize feeding behavior.

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A I want to thank Harry Kissileff for the opportunity to review the last 25 years of progress in the field of metabolic and hormonal controls of food intake. I have not been able to mention everyone who has made important contributions to the field. However, I have tried to identify a large number of important advances and a set of interesting conferences and publications that have influenced our thinking and experimental directions. Hopefully, I have been able to identify the major themes in the control of food intake by metabolic and hormonal signals in the last 25 years. I also want to thank Franc¸oise J. Smith for her valuable assistance in the preparation of the manuscript. I think the Columbia University Seminar on Appetitive Behavior is a unique treasure in our field. Those of us that have been privileged to participate in the Columbia University Seminar on Appetitive Behavior have been stimulated, challenged, and inspired in a unique open and collegial atmosphere. I wish the Columbia University Seminar on Appetitive Behavior continued good luck in the coming 25 years.

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