The adipocyte: a model for integration of endocrine and metabolic signaling in energy metabolism regulation. Am J Physiol Endocrinol Metab 280: E827-E847, 2001.-The ability to ensure continous availability of energy despite highly variable supplies in the environment is a major determinant of the survival of all species. In higher organisms, including mammals, the capacity to efficiently store excess energy as triglycerides in adipocytes, from which stored energy could be rapidly released for use at other sites, was developed. To orchestrate the processes of energy storage and release, highly integrated systems operating on several physiological levels have evolved. The adipocyte is no longer considered a passive bystander, because fat cells actively secrete many members of the cytokine family, such as leptin, tumor necrosis factor-␣, and interleukin-6, among other cytokine signals, which influence peripheral fuel storage, mobilization, and combustion, as well as energy homeostasis. The existence of a network of adipose tissue signaling pathways, arranged in a hierarchical fashion, constitutes a metabolic repertoire that enables the organism to adapt to a wide range of different metabolic challenges, such as starvation, stress, infection, and short periods of gross energy excess. leptin; tumor necrosis factor-␣; interleukins; obesity; insulin resistance OVERVIEW Unraveling the diverse hormonal and neuroendocrine systems that regulate energy balance and body fat has been a long-standing challenge in biology, with obesity as an increasingly important public health focus (12). Adipose tissue is the body's largest energy reservoir. For example, an adult with 15 kg of body fat has Ͼ460 MJ (110,000 kcal) of lipid fuel stores, which could provide 8.37 MJ (2,000 kcal) daily for ϳ2 mo (75, 129). The primary role of adipocytes is to store triacylglycerol during periods of caloric excess and to mobilize this reserve when expenditure exceeds intake. Mature adipocytes are uniquely equipped to perform these functions. They possess the full complement of enzymes and regulatory proteins needed to carry out both lipolysis and de novo lipogenesis. In fat cells, the regulation of these processes is exquisitely responsive to hormones, cytokines, and other factors that are involved in energy metabolism (87). The ability to carry out these functions is acquired during embryonic development in preparation for the postnatal period, when an adipose energy reserve becomes necessary. Major expansion of the white adipocyte population is delayed until shortly after birth, although preadipocytes first appear late in embryonic life (22).The present review will focus on the evidence for the synthesis and secretion by white adipocytes of endocrine, paracrine, and autocrine signals implicated in energy balance regulation, with special reference to cytokines. The interactions between these adipose tissue-derived mediators and other neuroendocrine pathways will be examined. Furthermore, the metabolic alterations in adipose tissue signaling leading...