Regulating food intake.

EVERY ORGANISM INGESTS FOOD (energy). If it takes in too little, it will starve; if it takes in too much, it will become obese. Too little is readily defined as caloric intake less than expenditure, and too much is simply the opposite. Multiple regulatory pathways are known that promote and inhibit feeding and thus regulate energy balance. However, these pathways and their interactions remain incompletely understood. As we are in the midst of an epidemic of obesity, there is considerable urgency to understand how food intake is regulated. Recent publications in the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology have addressed a number of important questions in this field. Monogenic obesity, such as the various loss of function mutants of leptin and its receptors, is rare outside the laboratory. Much of human obesity is instead multifactorial and usually involves relative overconsumption. Both internal and external factors contribute to this overconsumption. As with humans (17), so with rats (16), palatability of a meal affects the amount consumed, the rate of consumption, and subsequent metabolic processing. Rats given a diet with highenergy density (typically a high-fat diet) can be separated a posteriori into individuals that are susceptible or resistant to diet-induced obesity (18), and selective breeding indicates that this is a polygenic trait. Commerford et al. (7) could show no difference in lipogenic capacity or dietary fat retention between obesity-prone and obesity-resistant rats. Accordingly, they concluded that increased energy intake was necessary for the accelerated weight gain. Both energy density and palatability of the diet appear to contribute independently to weight gain (19). Recent work also addresses the question of why some individuals are more responsive than others to changes in caloric intake. Leptin is secreted by white adipocytes in proportion to fat mass and is thus well suited to signal energy content (36). Acting centrally, leptin reduces food intake and increases energy expenditure. However, it is well known that diet-induced obesity is associated with leptin resistance. A study by Lin et al. (21) demonstrated rapid induction of leptin resistance when rats were switched from a lowto a high-fat diet and vice versa. These results were interpreted to indicate that dietary fat per se may induce leptin resistance. In another study, leptin sensitivity was assessed before exposure to highenergy diet. Those rats with the lowest leptin sensitivity (i.e., leptin resistance) had the largest subsequent weight gain, indicating that leptin resistance predicts diet-induced obesity (20). Despite the emphasis on diet-induced obesity, these and other studies also highlight the extent to which body weight is regulated and some of the variables that are monitored to do so. Sequential dietary manipulation showed that both obesity-prone and obesity-resistant rats defend their body weights (19). Female musk shrews, which have little stored energy, must monitor multiple variables related to energy availability to ensure that mating occurs when available energy is adequate (31). Many species increase and decrease their body weights and adiposity on a photoperiodic, circannual basis (9, 22, 23). The king penguin fasts for extended periods while incubating its egg. A switch from fatty acid to protein catabolism appears to be perceived as a “refeeding signal” (5). Feeding the fructose analog 2,3-anhydro-D-mannitol stimulates food intake in rats fed a low-fat, but not a high-fat, diet (13). Magnetic resonance spectroscopy, both in vivo (13) and in vitro (14), indicates that the analog depresses hepatocyte ATP content to a lesser extent on the high-fat diet, thus minimizing the putative feeding signal. Orexin-A and orexin-B (also known as hypocretins-1 and -2) were so named because they are synthesized only in a small group of neurons in the lateral hypothalamus, a region of the brain long known to be an important contributor to feeding behavior. Although they are indeed orexigenic, they have multiple actions, as illustrated by several reports in the journal. Orexin-B depolarizes postsynaptically both parvocellular and magnocellular neurons on the hypothalamic