In parallel to the studies of rodent thermogenic adipose tissue, efforts to understand the importance of BAT in humans have continued. Notably, Becher et al. determined that the presence of BAT in adult humans is linked to the incidence of cardiometabolic disease (9). Individuals with detectable BAT had lower prevalence of type 2 diabetes, dyslipidemia, congestive heart failure, and hypertension, across different ranges of BMI. This observation is exciting as it supports the hypothesis that BAT can regulate cardiometabolic health, even independent of its potential effect on body weight. Nevertheless, correlation, of course, does not equal causation. As such, the physiological importance of BAT in adult humans and the potential contribution of BAT dysfunction to the development of metabolic disease has remained a topic of great discussion. In June of 2023, organizers of the annual meeting of the Endocrine Society (ENDO 2023) staged a live debate, where leading investigators in the study of human BAT offered their perspectives on the burning question of whether human BAT is a viable target for treatment of cardiometabolic disease. In this issue of the JCI, these same investigators expand on the discussion, highlighting the challenges (Carpentier and Blondin) and promise (Cypess) of human BAT as a therapeutic target (10, 11).

Carpentier and Blondin question the physiological importance of human BAT during acute cold exposure, as the amount of BAT is relatively small in comparison with rodents and cold exposure invokes a multi-organ response (e.g., shivering thermogenesis) in which the contribution of BAT may be minor. Moreover, they raised concerns as to whether 18F-FDG uptake truly reflects BAT thermogenesis, particularly in older or diabetic subjects, arguing that glucose uptake and metabolism may not be directly coupled to thermogenesis. As such, they question whether there is sufficient evidence that BAT dysfunction contributes to development of metabolic disease. Substrate preference for BAT thermogenesis has been a topic of discussion. The development of improved stable isotope tracing techniques is now enabling investigators to elegantly trace nutrient fate and identify critical fuels of thermogenesis in adipocytes (12, 13). Emanating from these emerging studies is an appreciation of the flexibility of brown adipocytes with respect to fuel selection and the importance of nutritional state (fed versus fasted) in determining the preferred fuel choice (10). Multiple factors may influence substrate utilization in BAT. For example, mice display a diurnal rhythm of BAT thermogenesis, including rhythmic futile creatine cycling, which is highest during the start of the active/dark period (14). Diurnal BAT activity may be an important factor to consider when studying the therapeutic potential of promoting BAT activity. Other additional experimental factors may need to be considered in the study of BAT thermogenic activity, such as the duration of cold exposure.

Cypess remains optimistic about the potential of pharmacological BAT activation to drive improvements in glucose and lipid homeostasis. Treatment of individuals with the FDA-approved β3-adrenergic receptor agonist, mirabegron, leads to an estimated doubling of BAT mass, increased energy expenditure, increased insulin sensitivity and insulin secretion, and elevated HDL (15). Increasing energy expenditure did not ultimately impact fat mass and body weight, perhaps due compensatory changes in food intake. Cypess acknowledges that activating BAT as a therapeutic for obesity is likely a big challenge; however, BAT activation through this mechanism may help in the treatment of glucose and lipid disorders. The choice of utilizing β3-adrenergic receptor agonists to activate BAT is logical. In mice, pharmacological activation of this receptor drives brown adipocyte activation and a substantial degree of energy expenditure. Nevertheless, there are still some limitations to this approach as a tool to study the potential of BAT. First, both white and brown adipocytes express the β3-adrenergic receptor. It is thus difficult to formally ascribe the beneficial effects of mirabegron solely to its direct action on BAT. Moreover, β3-adrenergic receptor agonism may not maximally activate BAT thermogenesis in humans. The thermogenic potential of this tissue may thus be underestimated. In fact, human brown adipocytes appear to be more responsive to β2-adrenergic receptor agonism (16). Moreover, the natural response of BAT to cold exposure is not entirely mimicked by agonism of adipocyte β-adrenergic receptors. In fact, β-adrenergic receptor–independent mechanisms enhancing BAT thermogenesis exist (17). Cold induces a notable remodeling of adipose tissue, including changes in immune cell composition and vascular remodeling (18). Immune cell–derived signals, in turn, amplify the effects of catecholamines on thermogenic gene activation. As such, the identification of new strategies to better mimic the wide-ranging effects of cold exposure on brown fat tissue — not just mature adipocytes — may enable investigators to test the true potential of this tissue.