A major new dimension emerged in the late 1970's with the establishment of a link between BAT and energy balance (Table 1). This resulted from two key observations, one of which was that rats exhibiting high rates of diet-induced thermogenesis on a cafeteria diet are characterized by an activation of BAT (Rothwell and Stock, 1979), including increased mitochondrial GDP binding indicative of an activation of the proton conductance pathway (Brooks et al., 1980). The other major observation was of decreased BAT activity, with a reduction in GDP binding, in obese (ob/ob) mice; this was proposed as a causative factor in the development of their obesity (Himms-Hagen and Desautels, 1978).

These pioneering observations resulted in a new paradigm in the etiology of obesity (Rothwell and Stock, 1981; Himms-Hagen, 1983, 1989; Trayhurn, 1989). A tissue and molecular basis for the reduced energy expenditure on facultative thermogenesis proposed as an important factor in the development of obesity had been identified. Abnormalities in BAT activity were subsequently reported in a range of animal obesities, including db/db mice and Zucker (fa/fa) rats, and in rodents with experimentally-induced obesity (Himms-Hagen, 1989; Trayhurn, 2017). The central role of BAT in nutritional energetics and body fat regulation was further evident from studies demonstrating changes in thermogenic activity in a range of physiological conditions—from fasting to lactation and photoperiod-induced seasonal changes in body weight (Trayhurn, 2017).

A widely debated question in the 1980's was the extent to which studies on laboratory rodents were relevant to energetics and obesity in humans. This was effectively two questions—whether reduced expenditure on thermogenesis underpins the development of human obesity, and whether BAT is present in adults and thus the potential locus of impaired thermogenesis. The first question has been the source of continuing debate, but what seems clear is that thermogenesis is not a major component of expenditure in adult humans (Wijers et al., 2007; van Marken Lichtenbelt and Schrauwen, 2011)—certainly compared with small rodents such as mice in the cold where it accounts for up to two-thirds of total expenditure (Trayhurn and James, 1978; Trayhurn, 1979).

In the early 1980's, BAT was considered, essentially on histological criteria, to be absent in humans after the first years of life. This parallels precocial species such as goats and sheep in which BAT, while abundant at birth, rapidly loses UCP1 and thermogenic capacity over the first weeks of postnatal life being replaced by white fat (Casteilla et al., 1987; Trayhurn et al., 1993). Until 2009, the widely held view was that BAT (or thermogenic adipocytes) is absent from adult humans, despite anatomical studies identifying multi-locular adipocytes (Heaton, 1972), and more critically: (i) UCP1 being identified in adipose tissue depots of adults, including elderly subjects (Lean et al., 1986a), (ii) activation of BAT being demonstrated in phaeochromocytoma patients (Ricquier et al., 1982; Lean et al., 1986b), and (iii) UCP1 gene expression in adipose tissue of adults, particularly in phaeochromocytoma (Bouillaud et al., 1988).

The lack of recognition that adults do contain active BAT was a key element in the decline of interest in the tissue by the 1990's. However, over the past decade several major developments have led to a renewed focus on BAT. First, studies from the late 2000's utilizing FDG-PET (fluorodeoxyglucose positron emission tomography), commonly employed to track tumor metastasis, have mapped areas of high glucose uptake which also contain UCP1, thereby firmly identifying active BAT in adults (Cypess et al., 2009; Virtanen et al., 2009; Moonen et al., 2019). Through such studies, increased BAT activity has been observed in response to multiple stimuli, including cold exposure (as in rodents), and administration of insulin and the β₃-adrenoceptor agonist mirabregon (van Marken Lichtenbelt et al., 2009; Virtanen et al., 2009; Orava et al., 2011; Ouellet et al., 2012; Cypess Aaron et al., 2015). Importantly, the thermogenic activity of the tissue has been shown to decline with age and increasing BMI (Cypess et al., 2009; van Marken Lichtenbelt et al., 2009; Pfannenberg et al., 2010; Moonen et al., 2019).

An important development over the past decade, although not on BAT as such, is the discovery of a third form of adipocyte—“brite” or “beige” (Petrovic et al., 2010; Wu et al., 2012; Carobbio et al., 2019). These fat cells contain UCP1, providing the potential for thermogenesis, and have some of the other molecular signatures of brown adipocytes (Petrovic et al., 2010; Wu et al., 2012). Beige adipocytes are found primarily within WAT depots, and are recruited particularly during cold-exposure and following β-adrenergic stimulation resulting in the “browning” of white fat (Carobbio et al., 2019).

A further advance comes from evidence suggesting that BAT plays an important role in metabolic homeostasis, the tissue being a major site of glucose disposal, insulin action and triglyceride clearance (Bartelt et al., 2011; Stanford et al., 2013; Bartelt and Heeren, 2014). A high capacity for glucose uptake, which can be stimulated by insulin and cold, is evident from FDG-PET studies. Roles for BAT in glucose homeostasis and triglyceride clearance have led to the proposition that reduced activity in the tissue may underlie the metabolic syndrome (Nedergaard et al., 2011; Bartelt and Heeren, 2014; Moonen et al., 2019).

An additional dimension is the function of BAT as a secretory organ. Apart from the release of fatty acids, brown adipocytes synthesize and secrete multiple peptide/protein factors, these “brown adipokines” paralleling the adipokines of white adipocytes (Villarroya et al., 2013, 2017). While the adipokinome of white fat cells numbers several hundred entities (Trayhurn, 2013), it is unclear whether the secretome from brown adipocytes is as extensive. The brown adipokinome includes classical adipokines such as leptin and IL-6 (Villarroya et al., 2013, 2017), but brown adipocytes are unlikely to be an important source of these factors.

A major driver behind the renewed interest in BAT relates to its potential as a therapeutic target to treat obesity. This reflects the revival of a concept current in the 1980's, but it is now based on the firm acceptance that the tissue is present, thermogenically active and exhibits plasticity in adults. The ability to recruit beige adipocytes within WAT has further added to the focus on BAT (Petrovic et al., 2010; Wu et al., 2012; Jespersen Naja et al., 2013; Sacks et al., 2013), or more strictly on UCP1-dependent adipocyte thermogenesis, as a therapeutic route in obesity. But how realistic is this?

Our understanding of the functions of BAT has continued to evolve and it is evident that the tissue has multiple actions beyond a core thermoregulatory role. Recognition of its involvement in nutritional energetics and the etiology of obesity in the late 1970's transformed perspectives on the tissue. Over the past decade there has been a renaissance of interest in BAT, following clear evidence of its presence and metabolic plasticity in adult humans. There is currently considerable focus on BAT as a therapeutic target in the treatment of obesity and its associated metabolic disorders, aided by the identification of beige adipocytes and the phenomenon of browning of WAT. However, it is suggested that in totality there are formidable barriers to this approach and that the stimulation and recruitment of thermogenic adipocytes is unlikely to provide a realistic anti-obesity/anti-metabolic syndrome strategy in the near-future.

The author confirms being the sole contributor of this work and has approved it for publication.