International Textbook of Obesity - part 3 pptx

CONCLUSION Methods of evaluating adiposity and adipose tissue distribution have advanced substantially in the past decade. Stimulated by the rising worldwide preva- lence of obesity, new methods are under develop- ment that promise to advance the field. The point has now been reached, however, at which excellent methods of quantifying fatness are available for application in field, clinical, and research settings. REFERENCES 1. Wang ZM, Pierson RN Jr, Heymsfield SB. The five level model: a new approach to organizing body composition research. Am J Clin Nutr 1992; 56:19—28. 2. Snyder WM, Cook MJ, Nasset ES, Karhausen LR, Howells GP, Tipton IH. Report of the Task Group on Reference Man. Oxford: Pergamon Press, 1975. 3. Pietrobelli A, Formica C, Wang ZM, Heymsfield SB. Dual- energy x-ray absorptiometry body composition model: re- view of physical concepts. Am J Physiol 1997; 271: E941—E951. 4. Moore FD, Oleson, KH, McMurray, JD, Parker HV, Ball MR, Boyden CM. The Body Cell Mass and its Supporting Environment. Philadelphia: WB Saunders, 1963. 5. Gallagher D, Heymsfield SB, Heo M, Jebb SA, Murgatroyd PR, Sakamoto Y. Healthy percent body fat ranges: an ap- proach for developing guidelines based upon body mass index. Am J Clin Nutr 200; 72: 694—701. 6. NIH. Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults-the evi- dence report. Obes Res 1998; 6: 54S. 7. Durnin JVGA, Womersley J. Body fat assessed from total body density and its estimation from skinfold thickness: measurements on 481 men and women aged from 16 to 72 years. Br J Nutr 1974; 32:77—97. 8. Heymsfield SB, Baumgartner RN, Pan SF. Nutrition assess- ment of malnutrition by anthropometric methods. In: Shils ME et al. Modern Nutrition in Health and Disease. Balti- more, MD: Williams & Wilkins, 1999: 903—922. 9. Roche AF. Anthropometry and ultrasound. In: Roche AF, Heymsfield SB, Lohman TG (eds), Human Body Composi- tion, Champaign, IL: Human Kinetics, 1996: 167—190. 10. Albu JB, Murphy L, Frager DH, Johnson JA, Pi-Sunyer FX. Visceral fat and race-dependent health risks in obese non- diabetic premenopausal women. Diabetes 1997; 46: 456—462. 11. Sjo¨ stro¨ m L. A computer-tomography based multicompo- nent body composition technique and anthropometric pre- dictions of lean body mass, total and subcutaneous adipose tissue. Int J Obes 1991; 15:19—30. 12. Heymsfield SB, Ross R, Wang ZM, Frager D. Imaging tech- niques of body composition: advantages of measurement and new uses. In: Emerging Technologies for Nutrition Re- search. Washington, DC: National Academy Press, 1997: 127—150. 13. Seidell JC, Oosterlee A, Thijssen M, Burema J, Deurenberg P, Hautvast J, Josephus J. Assessment of intra-abdominal and subcutaneous abdominal fat: relation between anthro- pometry and computed tomography. Am J Clin Nutr 1987; 45:7—13. 14. Heymsfield SB, Wang ZM, Baumgartner RN, Ross R. Hu- man body composition: advances in models and methods. Ann Rev Nutr 1997; 17: 527—528. 15. Depres JP, Ross R, Lemieux S. Imaging techniques applied to the measurement of human body composition. In: Roche AF, Heymsfield SB, Lohman TG (eds), Human Body Compo- sition. Champaign, IL: Human Kinetics, 1996: 149—166. 16. Forbes GB. Human Body Composition. New York: Springer- Verlag, 1987. 17. Schoeller DA. Hydrometry. In: Roche AF, Heymsfield SB, Lohman TG (eds) Human Body Composition, Champaign, IL: Human Kinetics, 1996: 25—44. 18. Behnke AR, Feen BG, Welham WC. The specific gravity of healthy men. JAMA 1942; 118: 495—498. 19. Heymsfield SB, Wang ZM, Withers R. Multicomponent molecular-level models of body composition analysis. In: Roche AF, Heymsfield SB, Lohman TG (eds) Human Body Composition. Champaign, IL: Human Kinetics, 1996: 129—148. 20. Going SB. Densitometry. In: Roche AF, Heymsfield SB, Lohman TG (eds) Human Body Composition. Champaign IL: Human Kinetics, 1996: 3—24. 21. McCrory MA, Gomez TD, Bernauer EM, Mole PA. Evalu- ation of a new air displacement plethysmograph for measur- ing human body composition. Med Sci Sports Exerc 1995; 27: 1686—1691. 22. Wang ZM, Deurenberg P, Wang W, Pietrobelli A, Baum- gartner RN, Heymsfield SB. Hydration of fat-free body mass: review and critique of a classic body composition content. Am J Clin Nutr 1999. 69: 833—841. 23. Wang ZM, Deurenberg P, Wang W, Pietrobelli A, Baum- gartner RN, Heymsfield SB. Hydration of fat-free body mass: new physiological modeling approach. 1999.AmJ Physiol 1999; 276: E995—E1003. 24. Mazess, RB, Barden H, Bisek J, Hanson J, Dual energy X-ray absorptiometry for total-body and regional bone- mineral and soft-tissue composition. Am J Clin Nutr 1990; 51: 1106—1112. 25. Siri WE. Body composition from fluid spaces and density: analysis of methods. In: Brozek J, Henschel A (eds). Tech- niques for Measuring Body Composition. Washington, DC: National Academy of Sciences—National Research Council, 1961: 223—244. 26. Friedl KE, DeLuca JP, Marchitelli LJ, Vogel JA. Reliability of body-fat estimations from a four-component model by using density, body water, and bone mineral measurements. Am J Clin Nutr 1992; 55: 764—770. 27. Roche AF, Guo S. Development, testing and use of predic- tive equations for body composition measures. In: Kral JG, VanItallie TB (eds) Recent Developments in Body Composi- tion Analysis: Methods and Applications. London: Smith- Gordon, 1993: 1—16. 28. Baumgartner RN, Chumlea WC, Roche AF. Impedance for body composition. Exerc Sport Sci Rev 1990; 18: 193—224. 29. Houtkooper LB, Lohman TG, Going SB, Howell WH. Why bioelectrical impedance analysis should be used for estima- ting adiposity. NIH Technology Assessment Conference. Am J Clin Nutr 1996; 64: 436S—448S. 96 INTERNATIONAL TEXTBOOK OF OBESITY 30. Chumlea WC, Guo SS. Bioelectrical impedance and body composition: present status and future directions. Nutr Rev 1994; 52: 123—131. 31. Nunez C, Gallagher D, Visser M, Pi-Sunyer FX, Wang ZM, Heymsfield SB. Bioimpedance analysis: evaluation of leg-to- leg system based on pressure contact foot-pad electrodes. Med Sci Sports Exerc 1997; 29: 524—531. 32. Tan YX, Nunez C, Sun YG, Zhang K, Wang ZM, Heyms- field SB. New electrode system for rapid whole-body and segmental bioimpedance assessment. Med Sci Sports Exerc 1997; 29: 1269—1273. 33. Kushner RF, Gudivaka R, Scholler DA. Clinical characteris- tics influencing bioelectrical impedance analysis measure- ments. Am J Clin Nutr 1996; 64: 423S—427S. 34. Guo SS, Chumlea WC, Coockram DB. Use of statistical methods to estimate body composition. Am J Clin Nutr 1996; 64: 428S—435S. 35. Jensen MD, Kanaley JA, Reed JE, Sheedy PF. Measurement of abdominal and visceral fat with computed tomography and dual-energy x-ray absorptiometry. Am J Clin Nutr 1995; 61: 274—278. 36. Heymsfield SB, Waki M. Body composition in humans: advances in the development of multicompartment chemical models. Nutr Rev 1991; 49:97—108. 37. Chettle DR, Fremlin JH. Techniques of in vivo neutron activation analysis. Phys Med Biol 1984; 29: 1011—1043. 38. Dilmanian FA, Weber DA, Yasumura S, Kamen Y, Lidofsky L. Performance of the neutron activation systems at Brook- haven National Laboratory. In: Yasumura S, McNeill KG, Woodhead AD, Dilmanian FA. Advances in in Vivo Body Composition Studies. New York: Plenum Press, 1990. 39. Cohn SH. In vivo neutron activation analysis: state of the art and future prospects. Med Phys 1981; 8: 145—153. 40. Kehayias JJ, Heymsfield SB, LoMonte AF, Wang J, Pierson RN Jr. In vivo determination of body fat by measuring total body carbon. Am J Clin Nutr 1991; 53: 1339—1344. 97EVALUATION OF HUMAN ADIPOSITY Part III Appetite Regulation and Obesity Prevention MMMM 7 Role of Neuropeptides and Leptin in Food Intake and Obesity Bernard Jeanrenaud and Franc¸oise Rohner-Jeanrenaud Lilly Corporate Center, Indianapolis, Indiana, USA and Geneva University School of Medicine, Geneva, Switzerland Interrelationships Between Hypothalamic Neuropeptides and Leptin in the Maintenance of Body Weight Homeostasis, or Evolution to Obesity It is now accepted that body weight homeostasis is maintained via a series of complex interactions that occur between the brain, the hypothalamus in par- ticular, and the periphery (1—3), notably via a hor- mone, leptin, synthesized in and secreted from adi- pose tissue (4). Secreted leptin, although it may have direct peripheral effects, exerts its action principally within the brain. Following its transport through the blood—brain barrier, possibly via the short lep- tin receptor isoform (ObRa), leptin reaches the hy- pothalamic area where it binds to its long receptor isoform (ObRb). Following a specific signaling cas- cade, leptin inhibits many of the orexigenic neur- opeptides, while favoring many of the anorexigenic ones, as discussed below. By doing so, leptin exerts its effects of decreasing food intake and body weight, increasing fat oxidation and energy expen- diture, thus favoring leanness (5—11). In the present review, the characteristics of the main orexigenic and anorexigenic neuropeptides will be summarized (Figure 7.1) and putative effects of leptin thereon described or, when such effects of leptin are defective, the main reasons for the estab- lishment of a state of obesity will be outlined (Fig- ure 7.2). OREXIGENIC NEUROPEPTIDES Effects of Neuropeptide Y (NPY) NPY is a 36 amino acid neuropeptide that is widely distributed in the brain. In the hypothalamus, it is synthesized in the arcuate nucleus and released in the paraventricular nucleus. It stimulates food in- take by binding to Y1 and /or Y5 receptor subtypes (12—14). This increase in feeding can be observed upon infusing the peptide intracerebroventricularly (i.c.v.) in normal rats and is accompaniedby a rapid, sustained and marked increase in body weight (15,16). Central NPY infusion also stimulates insu- lin secretion via an activation of the parasym- pathetic nervous system reaching the endocrine pancreas (17). Concomitantly, central NPY admin- istration increases the activity of the hypothalamo- pituitary-adrenal axis, with resulting hypercorticos- teronemia and increased susceptibility to stressful situations (15,17). Finally, central NPY reduces the activity of the efferent sympathetic nerves reaching brown adipose tissue, with resulting decrease in energy dissipation as heat (18,19). The metabolic consequences of the hormonal International Textbook of Obesity. Edited by Per Bjo¨ rntorp. © 2001 John Wiley & Sons, Ltd. International Textbook of Obesity. Edited by Per Bjorntorp. Copyright © 2001 John Wiley & Sons Ltd Print ISBNs: 0-471-988707 (Hardback); 0-470-846739 (Electronic) Figure 7.1 Diagram of food intake regulation by orexigenic and anorexigenic neuropeptides. Stimulators of food intake are depicted as increasing the diameter of a tube by exerting a pressure (;) from inside, with agouti-related peptide (AGRP) mainly exerting its action by inhibiting the melanocortin system (-MSH and MC4 receptor), the effect of which is to reduce this diameter. Inhibitors of food intake are depicted as reducing (9) the diameter of the tube, with AGRP having little effect on the melanocortin system, allowing the latter to largely contribute to reducing this diameter. NPY, neuropeptide Y; MCH, melanin concentrating hormone; ORE, orexins; -MSH, -melanocyte-stimulating hormone and the melanocortin-4 (MC4-R) receptor; CRH, corticotropin-releasing hormone, CART, cocaine- and amphetamine-regulated transcript; NT, neurotensin. Not all neuropeptides are represented. Solid lines indicate marked effects, dotted ones weak effects changes produced by central NPY infusion (in- creased plasma insulin and corticosterone levels) are increased adipose tissue and liver lipogenic ac- tivity, changes mainly due to hyperinsulinemia (15,16), together with decreased insulin-stimulated glucose utilization by muscles (15,16). This muscle insulin resistance is likely to be due to the combined NPY-induced hyperinsulinemia/hypercorticostero- nemia (1). It should be noted that the NPY-elicited effects are very marked when exogenous NPY is chroni- cally infused i.c.v., resulting in high central concen- trations of the neuropeptide. Physiologically, how- ever, it is thought that these changes are modest, occurring via the spontaneous fluctuations of hy- pothalamic NPY levels, which transiently change nutrient partitioning toward fat accretion and de- creased oxidation processes. This situation persists until leptin is secreted into the blood as a result of hormonal changes such as transient hyperin- sulinemia in response to meal taking. Secreted lep- tin reaches the brain and decreases hypothalamic NPY levels by exerting its negative feedback inhibi- tion on the expression and amount of this neur- opeptide (20—22). Experiments have shown, how- ever, that in addition to NPY, other brain neuropeptidic systems play a role in the regulation of food intake. Thus, in transgenic mice made defi- cient in NPY, the expected decrease in both food intake and body weight fails to occur (23,24). Trans- genic mice lacking the NPY-Y1 or Y5 receptor actually gain more weight, not less, than the con- trols. (25,26). This indicates that the regulation of food intake and body weight is redundant, i.e. that several pathways are implicated and that when one of them is knocked out, others take over to main- tain a normal body weight homeostasis. 102 INTERNATIONAL TEXTBOOK OF OBESITY Figure 7.2 Diagram of the central effects of leptin on food intake. Leptin is depicted as decreasing the diameter of a tube relative to a normal one (dotted lines), due to its dual effect of reducing ( ) the expression or amount of neuropeptides that stimulate food intake (neuropeptide Y, NPY; melanin concentrating hormone, MCH; orexin, ORE; agouti-related protein, AGRP) and of increasing (!) the expression or amount of neuropeptides that inhibit food intake (cocaine- and amphetamine-regulatedtranscript, CART; corticotropin- releasing hormone, CRH; the melanocortin system with proopiomelanocortin, POMC, -MSH and the melanocortin-4 receptor, MC4-R). The effect of leptin on food intake (FI) is accompanied by increased fat oxidation and energy (E) expendidure, the three parameters together producing leanness NPY and Obesity When considering the hormono-metabolic changes produced by central NPY, one realizes that experi- mentally produced increases in central levels of this neuropeptide reproduce most of the abnormalities observed in experimental or genetic obesity syn- dromes (15,16), as well as in human obesity. The pathological relevance of increased hypothalamic NPY levels in mimicking obesity syndromes is sup- ported by the observation that NPY expression and levels are indeed increased in the ob/ob, db/db obese mice and in the fa/fa obese rat (1,20—22). Increased NPY levels in ob/ob mice are due to the lack of synthesis and secretion of leptin in adipose tissue, the ob (leptin) gene being mutated. As a result of this mutation, plasma leptin levels are nil, leptin fails to exert its negative feedback on hypothalamic NPY levels which remain continually elevated maintain- ing, probably with other neuropeptides that are influenced by leptin, the obesity syndrome (1,27). In the db/db and the fa/fa obese rodents, the ob gene of adipose tissue is normal, but the long form leptin receptor is mutated in its intracellular (db/db) (5) or extracellular (fa/fa) (28) domain. Even though leptin is overproduced by adipose tissue, bringing about a state of hyperleptinemia, it cannot act centrally and hypothalamic NPY levels remain high. The latter, probably in concert with other neuropeptides, maintain the obesity syndrome (29). Effects of Melanin Concentrating Hormone (MCH) MCH is a cyclic neuropeptide comprising 19 amino acids which is present in many areas of the brain, notably in the lateral hypothalamus (30). Its name derives from its ability to cause melanosome aggre- gation in fish skin, an action which is antagonized by -MSH, the melanosome-dispersing factor. Re- cently, a role for MCH in the central regulation of food intake has been discovered, i.c.v. MCH 103ROLE OF NEUROPEPTIDES AND LEPTIN IN OBESITY administration increasing food intake in normal rats (31,32). As for the melanosome aggregation/ dispersion system, the action of -MSH is the oppo- site of that of MCH, resulting in decreased food intake (33). The antagonistic action of MCH and -MSH extends to the regulation of the hy- pothalamo-pituitary-adrenal (HPA) axis, MCH de- creasing plasma corticosterone and ACTH levels relative to controls, while -MSH does the contrary, increasing plasma corticosterone and ACTH levels. (33). I.c.v. administration of a single dose of MCH results in stimulation of food intake that is dose- dependent, lasts for about 6 hours (32,33), but is moderate in amplitude when compared to the effect of NPY (34). The feeding effect of central MCH administration is counteracted not only by -MSH as just mentioned, but also by glucagon-like peptide (GLP-1) and neurotensin (34). As is the case for NPY, central leptin administra- tion decreases hypothalamic MCH expression and prevents MCH-induced increase in food intake (35,36). However, contrary to what is observed with NPY, long-term central MCH administration fails to produce sustained increases in food intake or in body weight gain, thus obesity (32). This is in con- trast with the observation that, in the obese ob/ob mouse, hypothalamic MCH expression is increased and may participate in the final development of the obese phenotype (31). To strengthen the physiological role of MCH in food intake regulation, mice carrying a targeted deletion of the MCH gene have been produced. When compared to controls, these mice are hy- pophagic, leaner, have decreased carcass lipids, and increased metabolic rate (37). Thus, MCH does rep- resent an important hypothalamic pathway in the regulation of body weight homeostasis, a pathway further completed recently by the discovery of a 353 amino acid G-protein-coupled receptor, to which MCH specifically binds (38,39). Such a receptor is present in the hypothalamus and many other brain regions, in keeping with the several functions, be- yond the feeding behavior, that are under the influ- ence of MCH (38,39). Effects of Orexins Orexin A and B (from the Greek word for appetite) have been discovered recently and are also referred to as ‘hypocretins’ (due to their hypothalamic loca- tion and sequence analogy to secretin) (40,41). Orexin A (33 amino acids) and orexin B (28 amino acids) neurons are restricted to the lateral and pos- terior hypothalamus, whereas both orexin A and orexin B fibers project widely into different areas of the brain (42—45). The corresponding cloned recep- tors, OX1 and OX2, are found in the hypothalamus (ventromedial hypothalamic nucleus, paraventricu- lar nucleus) a distribution that is receptor-specific (41,46). The stimulatory effect of central administration of orexin on food intake is much weaker than that of NPY, and is smaller than that elicited by MCH. Orexin A is more potent than orexin B in eliciting feeding, and its effect is consistent, whereas that of orexin B is not (47, 48). When given peripherally, orexin A rapidly enters the brain by simple diffusion as it is highly lipophilic, while orexin B with its low lipophilicity is degraded, thus failing to reach the brain adequately (49). The fact that orexin B is easily inactivated by endopeptidases could be one of the reasons for its relative inefficiency in regula- ting food intake. In a way similar to what has been observed with NPY, some of the centrally elicited effects of orexin A, e.g. the stimulation of gastric acid secretion, are mediated by an activation of the parasympathetic nervous system, favoring anabolic processes (50). Leptin administration produces a diminution of orexin A levels in the lateral hypothalamus (51), a finding that is in keeping with the observation of the presence of numerous leptin receptors on orexin- immunoreactive neurons in the lateral hy- pothalamus (52). Additional data must be gathered for the physiological role of the orexin system in food intake regulation to be better understood. Effects of Opioids The endogenous opioid system has long been known to play a role in the regulation of ingestive behavior. The opioid peptides exert their action via a complex receptor subtype system implicating ka- ppa, mu and delta receptors for, respectively, dynor- phin, -endorphin and the enkephalins (53). The specific modulation of taste and food intake can be partly understood by the use of selective receptor subtype agonists and antagonists (54,55). Typically, 104 INTERNATIONAL TEXTBOOK OF OBESITY the central administration of opioid agonists stimu- lates food intake, decreases the latency to feed, in- creases the number of interactions with the food, favors fat as well as sucrose ingestion, and increases body weight gain (54,56—60). In contrast, the central administration of opioid antagonists does the re- verse, decreasing food intake and body weight (55,60—62). The three major types of opioid receptors, mu, kappa, delta, have been cloned and belong to the G-protein-coupled family. Recently, another recep- tor highly homologous to the opioid receptors, but one that does not bind any opioid peptide with high affinity, has been cloned (63). This opioid receptor- like (ORL-1) is widely distributed within the central nervous system (CNS), the hypothalamus, hip- pocampus, and the amygdala, in particular (64). The endogenous ligand for this opioid-like orphan receptor has now been isolated (63). It is called nociceptin (as it increases pain responsiveness), or orphanin FQ. It is an 18 amino acid peptide which resembles dynorphin A and has a marked affinity for ORL-1 (63—65). Nociceptin and ORL-1 thus constitute a new peptidergic system within the CNS, a system of potential interest as it is present not only in rodents, but also in humans (64,65). When given centrally, nociceptin stimulates food intake in satiated rats, an effect that is blocked by an opioid antagonist, naloxone. As naloxone does not act at the level of ORL-1, this indicates that stimula- tion of food intake by nociceptin involves, at some ill-defined steps, the function of the ‘classical’ opioid system (65). Microinjection of nociceptin into two brain areas implicated in food intake (the ven- tromedial hypothalamic nucleus and the nucleus accumbens) also results in increased in food intake (64). The physiopathological implications of these findings will soon be unraveled. Opioids and Obesity The susceptibility to diet-induced obesity in the rat is strain dependent. For example, some strains of rats (e.g. Osborne-Mendel) overeat and become obese when fed a diet rich in fat. Other strains (e.g. S5B/P1) are resistant to high fat diet-induced obes- ity (66). In this context, it is interesting that central administration of a kappa opioid receptor antagon- ist decreases the intake of a high fat diet in the obesity-prone rats, while it does not do so in the obesity-resistant ones. In contrast, the central ad- ministration of a kappa opioid receptor agonist increases the intake of a high fat diet in obesity- prone rats, while it increases the intake of any type of diet in obesity-resistant animals (66). It is thus conceivable that the sensitivity to opioids differs from strain to strain, possibly from species to spe- cies. It is also possible that, within the brain areas constituting the opioid system, the distribution of the opioids, that of their receptors, may vary from strain to strain. This may lead to a strain-specific opioid dependency of the food intake process and evolution to obesity (66). The likely importance of the opioid system in obesity is illustrated by the observation that the peripheral administration of compounds with po- tent opioid antagonistic activity to obese rats re- sults in rapid, marked and sustained decreases in food intake and body weight gain (67,68). ANOREXIGENIC PEPTIDES Effects of Cocaine- and Amphetamine-Regulated Transcript (CART) Cocaine- and amphetamine-regulated transcript (CART) is a recently discovered hypothalamic pept- ide which is regulated by leptin and is endowed with appetite-suppressing activity (69,70). In the rat, the CART gene encodes a peptide of either 129 or 116 amino acid residues (70). In contrast, only the short form of CART exists in humans (70). The mature peptide contains several potential cleavage sites and CART may be post-transcriptionally processed into several biologically active fragments. Thus, in most tissues studied, CART peptides are short, CART (42—89) being found in the rat hypothalamus (71). This tissue processing of CART resulting in neuropeptides of different lengths may indicate that different CART peptides have different biological functions (71). Acute i.c.v. CART administration to normal rats produces a dose-dependent decrease in food intake (69,72). CART also transiently decreases the NPY- elicited feeding response in normal rats (69). Finally, CART appears to have a tonic inhibitory influence on food intake, as treatment of rats with anti-CART antiserum results in increased food intake (69). CART is regulated, in part, by leptin as chronic 105ROLE OF NEUROPEPTIDES AND LEPTIN IN OBESITY peripheral leptin administration to the leptin-defi- cient ob/ob mice results in a definite augmentation of the low expression of CART measured in the hypothalamic arcuate nucleus of these animals, an increase that is paralleled by the observed decrease in body weight. CART expression is also markedly reduced in the genetically obese leptin-resistant fa/ fa rat, thus possibly playing a role in the hyper- phagia of this animal (69). The physiological and pathological importance of CART has yet to be substantiated, although preliminary results with chronic infusion of the neuropeptide appear to indi- cate that it markedly reduces food intake and body weight of both normal and obese rats. Effects of Corticotropin-releasing Hormone (CRH) Apart from its role as controller of the hy- pothalamo-pituitary-adrenal (HPA) axis, CRH, a 41 amino acid neuropeptide, also functions as a central effector molecule that brings about a state of negative energy balance and weight loss. This is due to the ability of central CRH to decrease food in- take (73), to increase the activity of the sympathetic nervous system and to stimulate thermogenesis (73—75). CRH also influences gastrointestinal func- tions, inhibiting gastric acid secretion and gastric emptying, processes that are controlled by the para- sympathetic nervous system (76—79). Chronic i.c.v. CRH administration in normal (73), genetically obese fa/fa rats (80), as well as in monkeys (81), decreases food intake and body weight, partly by acting on energy dissipating mechanisms. Central microinjections of CRH were shown to inhibit NPY-induced feeding (82), in keeping with the no- tion that the locally released CRH could restrain the effect of NPY and/or of other orexigenic signals. Leptin administration results in transient increases in hypothalamic CRH levels, thus potentially favor- ing the CRH effects just mentioned (22). The leptin effect on CRH could occur via its increasing CRH type 2 receptor (CRHR-2) expression in the ven- tromedial hypothalamus, as these receptors are po- tentially responsible for the CRH-mediated de- crease in food intake and sympathetic nervous system activation (83,84). The Melanocortin System and Effects of -Melanocyte-stimulating hormone (-MSH) Pro-opiomelanocortin (POMC) is the precursor of many different molecules, the melanocortins, among which are ACTH, -endorphin, the melanocyte-stimulating hormones (-,-,-MSH). The -melanocyte-stimulating hormone -MSH is a 13 amino acid peptide which binds with different affinities to five different subtypes of G-protein- coupled receptors. An involvement of -MSH in body weight homeostasis via an interaction with the melanocortin-4 (MC4), possibly the MC3 recep- tors, has been recently described. MC3 receptors are present mainly in the hypothalamus, MC4 re- ceptors throughout the brain and in the sympath- etic nervous system (85,86). When administered i.c.v. to normal rats, -MSH decreases food intake (34), as does the central administration of a stable linear analog of -MSH, NDP-MSH (87). The rela- tionships existing between the melanocortins, their receptor subtypes and feeding have been illustrated by studying synthetic melanocortin receptor agon- ists and antagonists, amongst which are the com- pounds called MTII and SHU9119 (85,88). The i.c.v. administration of the agonist MTII markedly and dose-dependently inhibits food intake, while that of the antagonist SHU9119 markedly and dose-dependently stimulates food intake process (85,89). The co-injection of equal concentrations of the agonist and of the antagonist results in a food intake that is identical to that of control rats (85). In addition, MTII inhibits or suppresses, depending on the dose, the feeding response elicited by neur- opeptide Y (85), in keeping with the observation that both MC3 and MC4 receptors are found in CNS sites in which NPY neurons are also present (90). The effect of -MSH in decreasing food intake is under the ‘tonic’ inhibitory influence from a melanocortin-receptor antagonist called ‘agouti-re- lated protein’ (AGRP). When an active fragment of AGRP is administered i.c.v. to rats, an increased food intake is observed. Moreover, when -MSH is similarly administered, the observed decrease in food intake is blocked by the further addition of AGRP (91). The fundamental importance of the MC4 recep- tors has been highlighted by obtaining transgenic 106 INTERNATIONAL TEXTBOOK OF OBESITY mice lacking the MC4 receptors (MC4-R-deficient mice). These mice (female and male) exhibit in- creased food intake and become obese. Both sexes have marked hyperinsulinemia, hyperleptinemia, with either normoglycemia (females) or hyper- glycemia (males), plasma corticosterone levels being normal. These data support the view that MC4 receptors are essential in the cascade of events nor- mally leading to decreased food intake and leanness (92). The decreased food intake produced by - MSH and the subsequent cascade of events sum- marized above is accompanied by a change in the activity of the sympathetic nervous system. Thus, activation of the MC3/MC4-receptor system by the agonist MTII administered centrally results in a marked, specific, dose-dependent activation of the sympathetic nerves innervating the brown adipose tissue, as well as the renal and lumbar beds, while no change in blood pressure or heart rate is observed (93). The combination of decreased food intake and increased sympathetic activation with likely in- crease in energy dissipation suggests that the melanocortin system is well adapted to play a role in decreases in body weight. Since the main central effects of leptin are to decrease food intake and body weight, and to in- crease energy dissipation, it has been postulated that this hormone could bring about these changes by influencing the melanocortin system. It is thus of interest to observe that the effect of leptin in de- creasing food intake is blocked by a MC4 receptor antagonist (SHU9119), and that pretreatment with the antagonist is able to prevent the effects of leptin in decreasing both food intake and body weight. This effect is specific as the antagonist did not affect the decreased food intake produced by another peptide (GLP-1) (94). Thus, the MC4-receptor sig- naling is important in mediating the effects of leptin. In keeping with this finding is the observation that the MC4 receptor agonist, MTII, which decreases food intake in normal animals, also suppresses the hyperphagia of the leptin-deficient ob/ob mice. This suggests that leptin acts via MC4 receptors and that in the absence of leptin, i.e. in ob/ob mice, the lack of signaling through MC4 receptors would be respon- sible for the increased food intake (95), a viewpoint that remains to be fully validated (96). When considering POMC (the precursor of melanocortins, of -MSH) and AGRP (the antag- onist of the MC4 receptor), it is of interest to ob- serve that the lack of leptin in the ob/ob mouse (or lack of leptin signaling in the db/db one) is accom- panied by a decrease in POMC expression and an increase in that of AGRP (97—99). Moreover, leptin administration leads to an increase in POMC ex- pression and a decrease in that of AGRP (100—103). It may thus be concluded that leptin decreases food intake and body weight, in part by favoring the action of melanocortin neuropeptide(s) at the MC4 receptor, while concomitantly preventing the in- hibitory influence of AGRP on this same receptor, a concept excellently reviewed elsewhere (102). This specific effect of leptin is probably additive to its inhibitory one on hypothalamic NPY levels, NPY being one of the most potent food stimulators as described above, and being co-expressed with AGRP within the arcuate nucleus of the hy- pothalamus (104). The Melanocortin System and Obesity Obesity, as mentioned above, may result from alter- ed functions of the MC4 receptors. This is illus- trated in a global fashion by the observation that when the melanocortin receptor agonist (MTII) is administered i.c.v. to fasted—refed hyperphagic mice, to obese ob/ob mice, to yellow (Ay) obese mice, to NPY hyperphagic mice, their respective hyper- phagia is largely canceled (95). In addition, it has been recently demonstrated that mice lacking POMC (hence lacking subsequent -MSH syn- thesis and its inhibitory effect on feeding via its binding to MC4 receptors) overeat and become obese, a situation partly reversed by an -MSH treatment (105). The yellow obese mouse is an interesting animal model that underlines the potential importance of the melanocortin system. As reviewed recently, the pigment produced by melanocytes in the skin is under the regulation of -MSH and a paracrine melanocyte signaling molecule called ‘agouti’ (from American Spanish ‘aguti’, meaning alternation of light and dark bands of colors in the fur of various animals). Agouti binds to MC1 receptors and de- creases their signaling, resulting in decreased cAMP levels, thereby inducing melanocytes to synthesize a yellow pigment (pheomelanin). -MSH binds to MC1 receptors and increases their signaling, result- ing in increased cAMP, thereby stimulating the syn- thesis of a black pigment (eumelanin). The classical agouti hair color of many species appears brown, although the ‘brown’ hairs are in fact black-yellow- 107ROLE OF NEUROPEPTIDES AND LEPTIN IN OBESITY [...]... Clement K, Guy-Grand B, Froguel P A frameshift mutation in human MC4R is associated with a dominant form of obesity Nat Genet 1998; 20: 1 13 114 International Textbook of Obesity Edited by Per Bjorntorp Copyright © 2001 John Wiley & Sons Ltd Print ISBNs: 0-4 7 1-9 88707 (Hardback); 0-4 7 0-8 46 739 (Electronic) 8 Regulation of Appetite and the Management of Obesity John E Blundell University of Leeds, Leeds,... Metabolic Predictors of weight gain Int J Obes 1999; 23: 37 —41 24 Caro JF, Kolaczinski JW, Zhang PL et al Leptin: the tale of an obesity gene Diabetes 1996; 45: 1455—1462 25 Macdiarmid JI, Cade JE, Blundell JE High and low fat consumers, their macronutrient intake, and body mass in- 26 27 28 29 30 31 32 33 34 35 36 37 dex: further analysis of the National Diet and Nutrition Survey of British Adults Eur... of children and both the diet composition and adiposity of the parents In one study, a high-risk group of children (one or two overweight parents) was compared with a low-risk group (no parent overweight) at 4.5 years of age The high-risk group was consuming a higher percentage of fat in their diet and a smaller percentage of carbohydrate (30 ) In an unselected sample of 4- to 7-year-old children (35 ... modulation of sauvagine- and CRF-induced inhibition of gastric emptying in rats Eur J Pharmacol 1990; 182: 35 7 36 2 80 Rohner-Jeanrenaud F, Walker CD, Greco-Perotto R, Jeanrenaud B Central corticotropin-releasing factor administration prevents the excessive body weight gain of genetically obese (fa/fa) rats Endocrinology 1989; 124: 733 — 739 81 Glowa JR, Gold PW Corticotropin releasing hormone produces profound... GA, Dietz WH Television viewing as a cause of increasing obesity among children in the United States, 1986—1990 Arch Paediatr Adolesc Med 1996; 150: 35 6 36 2 Prentice AM, Jebb SA Obesity in Britain: gluttony or sloth? BMJ 1995; 31 1: 437 — 439 Egger G, Swinburn B An ‘ecological’ approach to the obesity pandemic BMJ 1997; 31 5: 477—480 International Textbook of Obesity Edited by Per Bjorntorp Copyright ©... existence of a relationship between parental obesity and obesity in the offspring (28) In a retrospective cohort study of 854 subjects born between 1965 and 1971, obesity (defined as a BMI of 27.8 for men and 27 .3 for women) in later adulthood was compared with the medical records of the parents Among those who were obese during childhood, the chance of obesity in adulthood ranged from 8% (for 1- to 2-year-olds... le ron´ 110 INTERNATIONAL TEXTBOOK OF OBESITY geur obese Med/Sci 1998; 14: 907—9 13 ` 30 Skofitsch G, Jacobowitz DM, Zamir N Immunohistochemical localization of a melanin concentrating hormone-like peptide in the rat brain Brain Res Bull 1985; 15: 635 —649 31 Qu D, Ludwig DS, Gammeltoft S, Piper M, Pelleymounter MA, Cullen MJ, Mathes WF, Przypek R, Kanarek R, Maratos-Flier E A role for melanin-concentrating... of hypothalamic injection of melanocortin 4 receptor ligands Brain Res 1998; 809: 30 2 30 6 90 Mountjoy KG, Mortrud MT, Low MJ, Simerly RB, Cone 112 91 92 93 94 95 96 97 98 99 100 101 102 1 03 104 INTERNATIONAL TEXTBOOK OF OBESITY RD Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain Mol Endocrinol 1994; 8: 1298— 130 8 Rossi M, Kim MS, Morgan... Bodnar RJ Opioid-receptor subtype agonist-induced enhancements of sucrose intake are dependent upon sucrose concentration Physiol Behav 1997; 62: 121—128 Noel MB, Wise RA Ventral tegmental injections of a selec- ROLE OF NEUROPEPTIDES AND LEPTIN IN OBESITY 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 tive mu or delta opioid enhance feeding in food-deprived rats Brain Res 1995, 6 73: 30 4 31 2 Giraudo SQ,... in the central regulation of feeding behaviour Nature 1996; 38 0: 2 43 247 32 Rossi M, Choi SJ, O’Shea D, Miyoshi T, Ghatei MA, Bloom SR Melanin-concentrating hormone acutely stimulates feeding, but chronic administration has no effect on body weight Endocrinology 1997; 138 : 35 1 35 5 33 Ludwig DS, Mountjoy KG, Tatro JB, Gillette JA, Frederich RC, Flier JS, Maratos-Flier E Melanin-concentrating hormone: a . JD, Takemori AE et al. 4-Dimethyl- 4-( 3- hydroxy- phenyl)piperidines: opioid antagonists with potent anorec- tant activity. J Med Chem 19 93; 36 : 2842—2850. 68. Shaw WN. Long-term treatment of obese Zucker. a dominant form of obesity. Nat Genet 1998; 20: 1 13 114. 112 INTERNATIONAL TEXTBOOK OF OBESITY 8 Regulation of Appetite and the Management of Obesity John E. Blundell University of Leeds, Leeds,. normal rats (31 ,32 ). As for the melanosome aggregation/ dispersion system, the action of -MSH is the oppo- site of that of MCH, resulting in decreased food intake (33 ). The antagonistic action of MCH