Physiological Regulation of Appetite Physiological regulation of food intake

IN THIS ISSUE OF THE JOURNAL are published six papers that were submitted in response to the Call for Papers “Physiological Regulation of Appetite” (7, 17, 25, 27, 66, 86). In addition, four other papers in this series have been published in previous issues (13, 31, 47, 48). This Call for Papers celebrates the journal’s strong commitment to basic and translational research that contributes to understanding of the regulation of body weight in humans and other animals. Among the numerous and broad areas covered by American Journal of PhysiologyRegulatory, Integrative and Comparative Physiology, this field stands out both for the number of studies published and for their excellence. It is clear that body weight is closely regulated under most conditions (43), and this implies that energy consumption, the amount and quality that is eaten, must be matched to energy expenditure. If an imbalance develops between energy intake and output, then the consequences for the organism can be severe. A recent review has pointed out that availability of oxidizable fuel is a major regulator of fertility in female mammals (80). However, in a time of unprecedented wealth worldwide, we as a species are developing unprecedented girth. This too has profound consequences; as noted by Davy and Hall (21), there is a strong and presumably causal relationship between weight gain and development of hypertension. Active areas of research include signaling of body status to the brain, including both energy content and of digestive status; the properties of food—its constituents and taste; central processing of these and other inputs; and interactions between ingestive and other behaviors. The unit of food intake, and to a large extent fluid intake, is the meal. Consequently an accepted definition of what exactly constitutes a meal is a matter of some importance. Current methods for defining meals in rodents have been challenged recently. Zorrilla et al. (86) have developed a meal definition that performs significantly better than previous methods. The importance of both appetitive behavior (acquiring food) and consummatory behavior (eating what you have acquired and stored) was highlighted in several studies that employed different species of hamsters. Thus in Syrian hamsters, food deprivation induces hoarding rather than hyperphagia when food is restored. Leptin administered during the period of food deprivation attenuated the subsequent hoarding (8). Likewise in Siberian hamsters, injections into the third cerebral ventricle of agouti-related peptide (AGRP) induced a robust and prolonged increase in hoarding that was apparent at one tenth the dose required to induce feeding, suggesting that the primary effect of AGRP in this species is to trigger the search for food (22). A somewhat similar result was obtained after peripheral injection of ghrelin. Ghrelin is an orexigenic and appetitestimulating hormone that is secreted largely by the stomach. Exogenous ghrelin, at reasonable doses, induced an early increase in feeding and a prolonged increase in appetitive behaviors (39). Diet-induced obesity (DIO) refers to the propensity for some animals to overeat and gain weight (fat) when given a palatable diet that is rich in calories. Selective breeding has shown that the DIO phenotype is not simply the result of a primary hyperphagia (45). Outbred DIO rats demonstrate reduced anorectic sensitivity to leptin (62, 65) and to insulin (15). Studies with selectively bred DIO rats confirm the reduced leptin sensitivity (45) and suggest that this is a preexisting defect and not related to the reduction of leptin transport that occurs upon development of obesity. Other investigators tested this conclusion by adenoviral delivery of leptin gene into the third ventricle in DIO and diet-resistant (DR) rats (81). High-fat feeding reduced the responses to leptin in DR rats [as also for insulin sensitivity (15)] but abolished both anorectic and metabolic responses to leptin in DIO rats. Consistent with these findings, insulin injection resulted in rapid increases in circulating leptin in both DIO and DR rats but reduced food intake only in DR animals (70). An attempt to develop a mouse model of leptin resistance was complicated by strainand sex-dependent responses and by thermoregulatory imperatives in singly housed mice (6, 36). A major clinical problem in treatment of obesity is recidivism, the weight regain after dieting or food restriction that can exceed the amount lost during the period of restriction. A number of potential contributing factors have been addressed. A single 20-min restraint stress significantly altered subsequent responses of DIO, but not DR, rats. While intake of chow or high-energy diet was not altered by the stress, weight gain was reduced in DIO rats on chow and increased in DIO rats on high-energy diet (50). Both caloric restriction and exercise reduced food intake, body weight gain, and circulating leptin in male DIO rats; however, they had divergent effects on circulating insulin and on expression of orexigenic and anorexigenic hypothalamic neuropeptides (43). Exercising rats subjected to caloric restriction also displayed reduced, or at least delayed, weight gain when ad libitum feeding was restored (42). Dietinduced hyperphagia is greater in female than male rats, and attenuation of this hyperphagia by exercise is more complete in males (24). MacLean et al. (47, 48) studied outbred Wistar DIO rats, while Evans et al. (27) studied two other outbred strains—Long-Evans and Sprague-Dawley rats—that are susceptible to DIO. All three strains show enhanced metabolic efficiency during caloric restriction. All show rapid weight