I. A Historical Perspective
Understanding the biology of a body organ requires knowledge of location, morphology, regulation, and function. In contrast to other classic metabolic organs, such as skeletal muscle, WAT, and liver, the biology of BAT in humans has remained elusive since Gessner first described its presence in hibernators in 1551. The 1960s heralded a golden era of human BAT research that withered in the late 1980s with the view that significant deposits of BAT did not persist beyond childhood. In the last decade, unequivocal evidence of BAT in adult humans has led to resurgence in global research interest. Table 1 summarizes major developments in human BAT research.
Table 1. Timeline and Summary of Major Developments in Human BAT Research
At the beginning of the last century, anatomists described similarities between fat masses located in the dorsal and cervical region of human fetuses and fat depots in the interscapular area of hibernating mammals (10–12). It was, however, not until the 1960s that BAT was ascribed a regulatory role in thermogenenesis (13–18). It was proposed that BAT was a heat-producing tissue in small mammals and human infants, defending newborns from hypothermia. BAT is histologically and functionally distinct from WAT, and the presence of the facultative proton transporter UCP1 confers upon it the unique ability to generate heat through respiratory uncoupling (19).
The thermogenic properties of BAT originally were of interest only to a few scientists studying hibernating animals. Serial publications revealed a 6-fold increase in heat production from BAT after cold acclimatization in rodents, dissipating heat to the body via dense vascularization juxtaposing deep viscera (13, 20–22). The striking thermogenic capacity of BAT led some researchers to regard it as an electric blanket for animals in the cold (23). Because temperature changes are cues to food availability in nature, BAT studies were extended to investigating response to nutrient variations. In the 1970s, Rothwell and Stock (24) observed near identical morphological changes in BAT between cold-exposed and high-fat diet-fed animals. Heat production in BAT during cold exposure corresponded closely to that after high-fat feeding. The strong association between diet-induced thermogenesis (DIT) and cold-induced thermogenesis (CIT) in animals led to the proposal that BAT played a major role in both. Meanwhile, from human cadaveric studies, Heaton (25) found that BAT persisted up to the eighth decade of life. These findings led to the hypothesis that BAT failure could contribute to development of obesity in adult humans (26–29), resulting in a tripling of BAT publications between 1980 and 1982.
During this early phase of human BAT research, investigations were restricted to examining depots around the adrenal bed, a location accessible during elective abdominal surgery. This approach overlooked BAT in extra-abdominal locations, underestimating its abundance and distribution in adults. The scientific consensus at the time did not support a definite metabolic role in energy homeostasis in adult humans (30, 31), with Rothwell and Stock raising the doubt of “Whither brown fat?” (32). It was recognized there were major difficulties identifying BAT depots in humans and that the view would “continue to be controversial until a method for quantitative noninvasive measurement of total BAT thermogenesis is developed” (30, 33).
It took another 2 decades for such noninvasive methods to become available. PET scanning technology has ushered in a new era of metabolic imaging, catalyzing the resurgence in BAT research. The rebirth of human BAT research interest has been viewed as a renaissance in metabolic medicine (34). The research questions in human BAT are the same as those posed in the 1980s; however, the field has been enriched by advances and insights from animal studies in the intervening years. This review will integrate new knowledge from animal studies into an appraisal of its physiological significance in humans.