Recruiting Brown Adipose Tissue in Human Obesity

Obesity remains a major biomedical challenge with its associated diseases, particularly insulin resistance and type 2 diabetes, imposing a substantial and increasing burden on health care systems. In the U.S., one-third of adults are classed as obese (BMI ≥30), while in the U.K., which has one of the highest incidence rates in Europe, 25% are obese. Conceptually, the treatment of obesity is simple: energy expenditure must exceed energy intake. In the late 1970s it was proposed, primarily on the basis of studies on rats and mice, that reduced expenditure on adaptive heat production (thermogenesis) associated with a specialized fat tissue—brown adipose tissue (BAT)—is central to the development of obesity. Correspondingly, for a period, stimulation of heat production in BAT was seen as a potential therapeutic route for reversing obesity, and there was a search for agents that would stimulate the activity of the tissue.

In the four centuries following its identification, different roles have been attributed to BAT, but in the early 1960s the tissue was firmly identified as a thermogenic organ generating heat through nonshivering mechanisms. Heat is produced by dissipation of the proton gradient across the mitochondrial inner membrane resulting in the uncoupling of oxidative phosphorylation (1). This process, which is critically dependent on the mitochondrial uncoupling protein 1 (UCP-1), is stimulated by noradrenaline from the sympathetic innervation acting through β₃-adrenoceptors (1). The concept that BAT is not only a thermoregulatory organ but also implicated in the regulation of energy balance with reduced thermogenesis (cold- and diet-induced) leading to obesity emerged through studies on obese mice and from overfeeding experiments on rats given a cafeteria diet (2). There was little progress, however, in the application of this concept to studies of obesity in humans, and interest in BAT waned. This was despite evidence in the 1980s for the presence of UCP-1 and a capacity for the activation of the tissue in adults (3).

A renaissance of interest in BAT was catalyzed in the late 2000s following the putative identification of multiple sites of the tissue in adult humans from investigations using fluorodeoxyglucose positron emission tomography (FDG-PET) (4). Use of FDG-PET and the detection of UCP-1 in the same areas resulted in the definitive identification of BAT in many adults (5,6). Further FDG-PET studies demonstrated that BAT activity is inversely related to BMI as activity was lower in obese subjects than in lean subjects and declined in older individuals (7–9). Insulin stimulates glucose uptake into BAT in humans, and acute cold exposure activates the tissue, as in rodents (6,10–12). Prolonged intermittent cold exposure, tantamount to cold acclimation, has been shown to lead to the recruitment of BAT in young, lean subjects (13–15) (Fig. 1). In contrast, only a limited increase in BAT metabolic activity was evident in patients with type 2 diabetes, these individuals being also overweight and older than those in other studies (16). It has therefore been unclear whether BAT is inducible in obese subjects, particularly those of older age, with a resultant enhancement of nonshivering thermogenesis. This is, of course, central to the proposition that BAT is a rational target for the treatment of obesity.

Whether BAT can be recruited in obese humans is directly addressed in an article by Hanssen et al. in this issue of Diabetes (17). The authors used FDG-PET to assess glucose uptake into presumptive BAT and white fat depots in a group of obese subjects before and after short-term “cold acclimation.” Cold acclimation, amounting to exposure to 14–15°C for up to 6 h per day over 10 days, resulted in increased glucose uptake in BAT in 6 of the 10 subjects studied in which the tissue was evident. In one subject, BAT activity was also induced by cold acclimation where activity had been previously absent. As in other studies (7,8), BAT activity was inversely related to age both before and following cold acclimation. There was, however, no significant relationship between BAT activity and percent body fat (although an inverse trend was evident). In contrast to its effect on glucose uptake in BAT, cold acclimation did not increase glucose uptake into subcutaneous and visceral white fat depots, implying that “browning” had not occurred (or that brite/beige adipocytes are of limited physiological significance). In skeletal muscle, uptake was significantly increased in the triceps brachii but not in the scalene muscles, and increased translocation of GLUT4 to the sarcolemma was apparent.

Interestingly, the recruitment of BAT during cold acclimation was not associated with any elevation in total energy expenditure or in nonshivering thermogenesis. This may be a consequence of the modest increases in BAT observed, perhaps reflecting the limited acclimation stimulus that can be imposed on humans, or indicate that the tissue is only a minor contributor to expenditure in adults. The mean BMI of the subjects studied was 32.9 kg/m², with the highest being 36.8 kg/m²; whether BAT can be recruited in severely obese subjects is an open question, particularly in the face of tissue hypoxia. Increased glucose uptake in BAT in obese subjects following prolonged cold exposure should affect glucose homeostasis (plasma glucose is reduced in the cold) and prevent induction of the obesity-associated insulin resistance. Indeed, mouse studies have indicated that brown fat is a major organ in glucose disposal and important in relation to insulin sensitivity; it has also been implicated in triglyceride clearance (18,19).

A key role for BAT in metabolic regulation, particularly during or following cold exposure, suggests that a lack of the tissue or reduction in its activity could have a role in the metabolic syndrome as well as in obesity (18,19). BAT has certainly reemerged as a therapeutic target in obesity, and the strategy of using selective β₃-adrenoceptor agonists has met with some recent success (20). Alternative approaches have also been considered, including potentiation of the induction of brite/beige adipocytes, BAT transplantation, and stem cell therapy. Whether the more technically innovative strategies are at all feasible remains unclear. There is also uncertainty as to whether the expansion and activation of BAT, or browning of white fat depots, could ensure a sustained and sufficient impact on energy balance and do so without raising cardiovascular concerns.