Introduction thermogenesis. The latter, at least in rodents, involves The ability to assure continuous availability of energy the function of brown adipose tissue (BAT; Lowell and despite highly variable energy supplies in the environ-Flier, 1996). Unlike white adipose tissue, which is dement is a major determinant of the survival of all species. signed for energy storage, BAT is designed for the regu-For higher organisms including mammals, a solution to lated expenditure of energy as heat. Neural signals that this problem involved development of the capacity to emanate from the hypothalamus and are transmitted efficiently store excess energy as triglycerides in adiby the autonomic nervous system regulate this highly pose cells, from which stored energy could be rapidly innervated tissue, which employs the uncoupling protein released for use at other sites. In addition, physiological (UCP), a 32 kDa protein of the inner mitochondrial memmechanisms arose to enhance survival by stabilizing brane to uncouple mitochondrial respiration (Jezek et adipose energy stores during prolonged periods of defial., 1994). cient or excess nutritional availability. The outlines of Despite this highly regulated physiological system, such physiological systems are simple: with prolonged it is evident that obesity is currently an exceptionally nutritional deprivation, falling energy stores are sensed, common problem in humans, and the search for causal leading to increased food-seeking behavior and defactors has been intensifying. The last several years creased energy expenditure; with prolonged nutritional have produced breakthroughs in two obesity-related arabundance, food intake is reduced and energy expendieas of investigation: the identification of genetic loci ture is increased to avoid excessive energy storage, ie at which mutations cause obesity in rodents, and the obesity. The systems involved in such adaptations are identification of transcription factors that regulate the referred to as systems for regulated energy balance. differentiation, pattern of gene expression, and lipid A physiological system for regulation of energy balcontent of fat cells. This review is intended, first, to ance and avoidance of obesity would be expected to provide an up-to-date perspective on advances in these have several requirements. The first is a mechanism by two areas. The second goal of this review will be to which information on the level of energy stores in adidescribe recent work that may begin to link these prepose tissue can be sensed, and the resulting information viously distinct areas of investigation, that is, to explain relayed to regulatory sites elsewhere in the body. Alhow a disequilibrium in energy homeostasis caused by though a number of candidate mechanisms have been obesity genes may ultimately result in changes in fat described for a feedback signaling system reflecting cell number and lipid content. the amount of adipose energy stores (Schwartz et al., 1994), the existence of such a mechanism was made certain by the cloning of the ob gene and identification Obesity Genes The identification of five genes responsible for distinct of its encoded protein leptin (Zhang et al., 1994; see below). The second requirement is a mechanism where- syndromes of spontaneous monogenic obesity in mice (Table 1) has advanced our knowledge dramatically, and by such a signal can be received and integrated at one or more regulatory sites, most likely in the central nervous together with insights obtained through induced mutations, a preliminary view of a “wiring diagram” for the system. The hypothalamus has been known to be a key brain region for regulation of metabolism and energy …