Lafontan M. Historical perspectives in fat cell biology: the fat cell as a model for the investigation of hormonal and metabolic pathways. Am J Physiol Cell Physiol 302: C327-C359, 2012. First published September 7, 2011; doi:10.1152/ajpcell.00168.2011.-For many years, there was little interest in the biochemistry or physiology of adipose tissue. It is now well recognized that adipocytes play an important dynamic role in metabolic regulation. They are able to sense metabolic states via their ability to perceive a large number of nervous and hormonal signals. They are also able to produce hormones, called adipokines, that affect nutrient intake, metabolism and energy expenditure. The report by Rodbell in 1964 that intact fat cells can be obtained by collagenase digestion of adipose tissue revolutionized studies on the hormonal regulation and metabolism of the fat cell. In the context of the advent of systems biology in the field of cell biology, the present seems an appropriate time to look back at the global contribution of the fat cell to cell biology knowledge. This review focuses on the very early approaches that used the fat cell as a tool to discover and understand various cellular mechanisms. Attention essentially focuses on the early investigations revealing the major contribution of mature fat cells and also fat cells originating from adipose cell lines to the discovery of major events related to hormone action (hormone receptors and transduction pathways involved in hormonal signaling) and mechanisms involved in metabolite processing (hexose uptake and uptake, storage, and efflux of fatty acids). Dormant preadipocytes exist in the stroma-vascular fraction of the adipose tissue of rodents and humans; cell culture systems have proven to be valuable models for the study of the processes involved in the formation of new fat cells. Finally, more recent insights into adipocyte secretion, a completely new role with major metabolic impact, are also briefly summarized. history; adipocytes; insulin action; 3T3-L1 cells; glucose transport; fatty acids; lipolysis; catecholamines; preadipocytes SINCE THE EARLIEST TIMES, attention has been directed toward fat-related questions. It is currently accepted that the ability to store fat in adipose tissue was a major advantage for survival during cold winters and periods of food shortage for our "primitive" hunter ancestors. However, in modern societies, with increased food availability and nutritional efficacy, excessive fat deposition is frequently associated with degenerative or metabolic diseases. As early as 1901, life insurance companies noted that excess weight, particularly around the abdomen, was linked to reduced life expectancy. The risk was confirmed in the seminal studies of Vague (366) in Marseilles, who established the importance of abdominal (central) obesity in conferring excess mortality. The health hazard of obesity is not considered in the present review, which, rather, focuses on adipose tissue and adipocytes.