Peptides that regulate food intake.

IN THIS ISSUE OF THE JOURNAL are published the first group of papers submitted to the Special Call for Papers on the subject “Peptides that Regulate Food Intake.” These nine papers (7a, 32a, 37a, 37b, 41a, 42a, 43a, 46a, 49a) illustrate both the breadth and depth of the subject. They continue the contribution made by papers published in the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology toward understanding of the regulation of food intake and body weight. What are these peptides? How do they act? How do they interact among themselves and with other control systems? These are all important questions addressed by recent publications in this journal and highlighted below. Leptin is secreted by adipocytes and signals fat content to neurons in the arcuate nucleus of the hypothalamus. Leptin inhibits release of the potent orexigens neuropeptide Y (NPY) and agouti-related peptide (AgRP), which are coexpressed in neurons of the arcuate nucleus of the hypothalamus. Leptin also increases release, from adjacent neurons, of anorexigens -melanocyte stimulating hormone ( -MSH) and cocaineand amphetamine-regulated transcript (CART), which are also coexpressed (38). Food deprivation increases NPY and AgRP mRNA and decreases that of proopiomelanocortin (POMC) in the arcuate nucleus. These changes are largely reversed 6 h after refeeding (43), but not by leptin infusion or a palatable, noncaloric mash, indicating the importance of other postabsorptive factors (43). Zhang et al. (49) showed in several different fat depots of mice that leptin mRNA content varied directly with adipocyte volume, whereas messages for tumor necrosis factor, insulin receptor, and glucocorticoid receptor were all independent of cell volume. Obesity induced by feeding rodents a high-fat or high-energy diet is associated with leptin resistance; leptin becomes less effective at reducing food intake. The leptin resistance caused by changing from chow to a high-fat diet occurred rapidly and was apparent before any change of body composition could take place (26), suggesting that dietary fat, per se, can induce leptin resistance. Importantly, in rats maintained on chow, leptin sensitivity predicts the development of diet-induced obesity when the animals are subsequently placed on a high-energy diet (24). Rats with the lowest leptin sensitivity become most obese. Changes in circulating leptin can be of varying importance in different models of weight loss. For example, lactating sheep are in negative energy balance despite hyperphagia. Here the reduction of plasma leptin appears to be a primary signal for the hyperphagia (42). In contrast, the weight loss induced by acute stress, although associated with reduced circulating leptin, is unchanged when plasma leptin is clamped high (17). In addition to its effects on food intake, leptin also has significant metabolic actions. With the use of different strains of db/db mice having profound leptin resistance due to absence of the long form of the leptin receptor, it was possible to show some degree of metabolic signaling through short forms of the receptor (18). The same group showed with partial lipectomy experiments that leptin is not required for regulation of total body fat (16). A number of studies have explored other aspects of leptin’s function. Transduction of leptin signals in the arcuate nucleus proceeds through the JAK-STAT pathway (28). This pathway is also activated by removal of glucocorticoids (adrenalectomy) with resulting enhancement of the anorectic response to leptin (28). Peripheral (intraperitoneal) CCK augmented weight loss in response to intracerebroventricular infusion of leptin, but did not alter the anorectic response to the leptin infusion (29). Central interactions were also addressed. Injection of urocortin, the natural ligand of CRH type 2 receptors (44), in the hypothalamic paraventricular nucleus reduced food intake and increased plasma leptin compared with pair-fed control animals (22). Similarly, injection of the opioid antagonist naltrexone into the nucleus of the solitary tract reduced body weight and food intake and increased plasma leptin compared with pair-fed controls (12). Arcuate NPY/AgRP neurons project to the lateral hypothalamus and to the paraventricular nucleus (38). The latter nucleus tends to be a site where feedinginhibitory inputs are processed (45, 50). Thus urocortin and CRH injected into the paraventricular nucleus reduced feeding induced by food deprivation or by NPY (45). Altered hypothalamic NPY signaling is evident in several models of obesity and in senescence. The Otsuka Long Evans Tokushima Fatty rat lacks the CCK-A receptor, which is a satiety signal (6). It overeats, developing obesity with elevated arcuate NPY and POMC messages. Pair-feeding with lean controls normalized body weight and arcuate NPY and POMC labeling, but resulted in increased NPY mRNA in the dorsomedial nucleus of the hypothalamus (6). Interestingly, increased NPY mRNA in the dorsomedial nucleus was also seen at 18, but not at 6, days postpartum in lactating ewes (42). When rats with diet-induced obesity were switched from high-energy diet to chow, they displayed reduction of food intake and reduced POMC and dynorphin, but not NPY, mRNA in the arcuate nucleus (23). This group subsequently reported Address for reprint requests and other correspondence: W. A. Cupples, Lady Davis Institute, SMBD-Jewish General Hospital, Montreal, Quebec, Canada, H3T 1E2 (E-mail: [email protected]). Am J Physiol Regul Integr Comp Physiol 284: R1370–R1374, 2003; 10.1152/ajpregu.00129.2003.