The adipocyte: Storage depot or node on the energy information superhighway?

In a world where food availability is intermittent, survival requires the capacity to store ingested calories in excess of immediate requirements so that energy may be released at a later point upon demand. To orchestrate these processes of energy storage and release, highly integrated systems have evolved, and these operate on several physiological levels. As for many complex physiologic systems, the brain provides an essential coordinating role. Most important are the hypothalamic centers (see Figure 1) that coordinate energy homeostasis through regulation of food intake (hunger and satiety), energy expenditure (thermogenesis), and the secretion of hormones (especially insulin) that regulate substrate interconversion, storage, and mobilization. But where does the energy storage take place? Enter the adipocyte, and along with it obesity, a remarkably prevalent disorder that is defined as a state of pathologically increased adipose cell mass. Is the adipocyte an innocent bystander, or does it play an active role in the regulation of energy homeostasis and body composition? Although adipose cell enlargement and eventual hypertrophy are the defining features of obesity, the adipocyte has been viewed as a largely passive participant in the disease process, accumulating or losing lipid stores in response to alterations in substrates and regulatory signals produced at distant sites. As a cell type, therefore, the adipocyte has received a great deal of attention only recently, and obesity, the dominant disease affecting adipocyte function, has lacked major breakthroughs in the realm of molecular pathogenesis. Indeed, much of the important research in obesity hastaken place in departments of psychology and psychiatry. Recent advances in the area of adipocyte development and evidence that the adipocyte can function as an endocrine cell have promised to change this situation radically and permanently, and these are the subject of this minireview. The Black Box of Energy Balance Viewed broadly, obesity is a disorder of energy balance, occurring when energy intake chronically exceeds energy expenditure. It is now clear that in normal physiology, these two components of the energy balance equation (i.e., energy intake and expenditure) are linked, not independent, variables. When food intake increases, so does energy expenditure, and vice versa. Teleologically, this could be viewed as a mechanism to conserve calories when food deprived and to prevent obesity when excess food is ingested. Much has been learned about the mechanism by which chronic overfeeding increases energy expenditure beyond the energetic costs of digestion, absorption, metabolic interconversions, and carrying around the extra weight. This adaptive thermogenesis involves the activation of the sympathetic nervous system, and, at least in rodents, subsequent stimulation of heat production in brown adipose tissue (BAT) (Himms-Hagen, 1989). BAT is the physiologic opposite of white adipose tissue, being designed to burn, not store, energy, and to release the energy as heat. BAT accomplishes this through a unique mitochondrial protein (thermogenin, or uncoupling protein) that uncouples fuel oxidation from ATP generation by collapsing the hydrogen ion gradient across the inner mitochondrial membrane (Nicholls and Locke, 1984). The recent demonstration that animals made deficient in BAT through a transgenic toxigene (Lowell et al., 1993) developed not only efficient metabolism and obesity but hyperphagia as well, strongly suggested that food intake and energy expenditure are linked through BAT, via an as-yetunknown signaling mechanism. The existence of such a physiologic link between energy intake and expenditure has also been suggested by several of the genetic models of spontaneous obesity in rodents that have been studied for the past 30 years (Bray and York, 1979; Friedman and Leibel, 1992). In these single-gene autosomal recessive disorders (ob/ob, db/db), severe obesity is always accompanied by both hyperphagia and diminished energy expenditure, the latter associated with BAT dysfunction due to inadequate stimulation by the sympathetic nervous system. The molecular link between excessive food intake and decreased energy expenditure, although fundamental, has remained obscure. Since closely apposed hypo-