Brown Adipose Tissue - role in metabolic disorders

Brown adipose tissue, a thermogenic organ, previously thought to be present in only small mammals and children has recently been identified in adult humans. Located primarily in the supraclavicular and cervical area, it produces heat by uncoupling oxidative phosphorylation due to the unique presence of uncoupling protein 1 by a process called nonshivering thermogenesis. BAT activity depends on many factors including age, sex, adiposity and outdoor temperature. Positron-emission tomography using 18F-fluorodeoxyglucose and computed tomography (18F-FDG PET–CT), magnetic resonance imaging (MRI) and thermal imaging (IRT) are among several methods used to detect BAT in humans. The importance of BAT is due to its role in whole body energy expenditure and fuel metabolism. Thus it is postulated that it may be useful in the treatment of metabolic diseases. However, there are still many unanswered questions to the clinical usefulness of this novel tissue. 
IMC J Med Sci 2019; 13(1): 002


Introduction
The rediscovery of functional brown adipose tissue (BAT) in adult humans has generated interest in its potential as a therapeutic target to improve metabolic health. BAT is a thermogenic organ located primarily in the supraclavicular area in adult humans. Smaller deposits are also located in the paravertebral, perinephric and mediastinal areas [1][2][3][4]. They possess uncoupling protein 1 (UCP-1) which acts as an alternate proton channel through which hydrogen ions travel down the electrochemical gradient, bypassing adenosine triphosphate (ATP) synthase and dissipating energy as heat [5,6]. This process is called nonshivering thermogenesis and is activated by cold and regulated by the sympathetic nervous system [6,7]. Several studies have demonstrated that this thermometabolic organ contributes to whole body energy expenditure [8][9][10][11] and plays a role in glucose [11] as well as lipid metabolism [12]. There is ongoing research to explore the role of BAT in diseases such as type 2 diabetes mellitus, dyslipidaemia and nonalcoholic fatty liver disease. This review aims to highlight the morphology, location, mechanism of action, detection and clinical usefulness of BAT.

Morphology
BAT is richly vascularized and densely innervated by terminal fibres of the sympathetic nervous system. It is characterized by polygonal cells with a central nucleus and multiple, small vacuoles that store triglycerides (i.e. multilocular lipid droplets). They are characteristically rich in large, spherical UCP-1 containing mitochondria. UCP-1 is uniquely expressed in the inner mitochondrial membrane and is essential in the uncoupling of mitochondrial oxidative phosphorylation [5].

Location and amount of BAT
BAT is strategically located around major blood vessels to ensure adequate delivery of substrates and effective dissipation of heat throughout the body [13]. Infants and children have a considerable amount of active BAT which gradually regresses with age, especially after puberty [14]. In infants, BAT consists of around 1-5% of their body weight [15] and is predominantly found in the interscapular region. Retrospective studies under non-cold stimulated conditions have found that 18 Ffluorodeoxyglucose ( 18 F-FDG) uptake is present in 6.8-8.5% of adults [1,16,17]. Out of these adults with detectable BAT activity, 18 F-FDG uptake is most commonly observed in the supraclavicular and cervical area (94.2%), paravertebral area (61.6%), mediastinal/para-aortic (28%) and perirenal areas (20.1%) [17]. Histological examination of tissue from the supraclavicular region has confirmed the presence of BAT [1][2][3][4]8,16,17]. The estimated amount of active BAT found in adult humans ranges from 4 to more than 1500 ml [18].

Mechanism of nonshivering thermogenesis
As noted earlier, BAT is characterized by an abundance of UCP-1 containing mitochondria. UCP-1, a six-domain transmembrane protein, is central to the production of heat by nonshivering thermogenesis. The expression of UCP-1 can be enhanced by adrenergic stimulation and peroxisome proliferator-activated receptor-γ (PPARγ) agonists [6]. Factors that can increase the metabolic activity of BAT include the use of sympathomimetics, β adrenergic agonists and cold exposure [6,7,[19][20][21]25]. During BAT activation, there is upregulation of UCP-1, which allows protons to travel down the electrochemical gradient while bypassing the ATP synthase. As a result of this uncoupling of oxidative phosphorylation, ATP is not synthesized and energy is dissipated as heat. With less ATP production, there is no negative feedback inhibition of the respiratory chain, producing a futile cycle [6] (Figure 1).

Factors associated with BAT activity in humans
In addition to the cooling protocol, the prevalence of BAT also depends on age, sex, adiposity and outdoor temperature [17]. Age is an independent negative predictor of BAT activity and mass, with BAT being more prevalent in younger individuals [2,10,16,17,22,23]. However, the cause of this age-dependent decline in BAT is currently unknown, but changes in sex and thyroid hormones as well as the activity of the sympathetic nervous system associated with increasing age have been speculated to be contributing factors [24]. Females have been observed to have more BAT activity and mass compared to males in some studies [16,17,22] but not all studies [23,25,26]. The difference in the prevalence of BAT between males and females may be due to the different effects of sex hormones on BAT activity [22] and the fact that females start to shiver at a higher temperature compared to males [27]. Body mass index (BMI), central obesity, body fat percentage and visceral fat are consistently lower in people with detectable BAT activity [2,10,16,23,28,29]. BMI is not only negatively correlated with BAT, but is also an independent predictor [1,2,[16][17]28]. Whether increased BAT activity results in a lower BMI or vice versa is still not known. Nahon and colleagues reported that larger individuals with higher lean mass require exposure to lower temperatures to activate cold-induced thermogenesis due to higher basal heat generation in this population. As such, studies investigating the relationship between BAT and adiposity should consider body size, composition and energy expenditure when designing coldinduced thermogenesis studies [30]. BAT is more likely to be detected during the winter compared to summer [1,2,31]. In addition, BAT activity and mass is inversely related with outdoor temperature at the time [1] or day [17,32] of the scan. These studies show that lower outdoor temperature is associated with increased BAT prevalence, volume and activity.

Methods of BAT detection
Multiple imaging modalities have been utilized to characterize and differentiate BAT from surrounding tissues based on its unique anatomical and functional properties. These techniques include 18 F-FDG PET-CT, magnetic resonance imaging (MRI), infrared thermography (IRT) and autonomous temperature sensors (i.e. iButtons). A detailed review outlining recent advances in BAT detection has recently been published by our group and therefore will only be briefly discussed [33]. 18 F-FDG PET-CT is the current reference standard in the detection of BAT. This modality measures the uptake of a glucose analogue (i.e. 18 F-FDG) that is taken up by BAT but is not metabolized [34]. Moreover, PET-CT has been instrumental in advancing our knowledge in the identification, location and nature of BAT [1][2][3]8,16,17]. However, a major limitation of PET-CT is the significant and unnecessary exposure to ionizing radiation precluding its use in large cohorts and in children [35]. Thus, alternative modalities including MRI have been utilized in the detection of BAT. The use of this technique is dependent on the morphological differences between BAT and surrounding tissues resulting in unique MR signatures which can be measured using fatfraction (FF) and T2* relaxation (T2*). Generally, BAT is characterized by smaller FF and T2* values due to its lower lipid content, greater vascularization and abundance of iron-rich mitochondria. In addition, both FF and T2* can also be used to measure BAT metabolic activity as reductions in these parameters have been associated with 18 F-FDG uptake [36]. Imaging modalities that measure changes in skin temperature including IRT and autonomous temperature sensors have been used to detect BAT [13]. These techniques rely on the heat produced by BAT via non-shivering thermogenesis in the overlying skin when activated. However, the use of these modalities in measuring BAT activity is often confounded by skin thickness, increased blood flow and muscle activity upon cold exposure. As such, further investigation is warranted before these modalities can be widely adapted in the measurement of BAT. Other emerging modalities are currently being developed to measure BAT. However, these methods are of limited availability, expensive and still in their infancy. Examples include detection of BAT using hyperpolarized MRI [37,38], contrast ultrasound, near-infrared fluorescence imaging [39] and nearinfrared time-resolved spectroscopy.

Therapeutic potential
As alluded above, BAT presence and activity is negatively associated with weight and central adiposity, suggesting a possible role of this tissue in the context of obesity [8][9][10][11]29]. In addition, when BAT is activated, it uses endogenous derived fatty acids, free fatty acids [12,41] and glucose [11] as its fuel source, suggesting that this thermometabolic organ contributes to wholebody energy homeostasis. A study by Iwen and colleagues demonstrated that cold-induced BAT activation resulted in increased peripheral glucose uptake and higher insulin sensitivity without influencing pancreatic hormone secretions [41]. As such, it is not surprising that fasting blood glucose is lower in those with BAT than those without; and BAT activity is inversely correlated with fasting glucose concentration [16,[41][42][43]. Chronic cold exposure induces weight loss [44] and increases insulin sensitivity by activating BAT in humans [45,46]. Recent studies showing metabolic improvement independent of thermogenesis after BAT transplantation in mice postulate that BAT is an endocrine organ, secreting cytokines such as IL-6 and FGF21 which have beneficial effects on other organs of the body [47,48]. Therefore, BAT shows potential in the treatment of not only obesity, but also diabetes mellitus, dyslipidaemia and nonalcoholic fatty liver disease and thus warrants further investigation.

Conclusion
There has been considerable research over the last few decades demonstrating the morphology, mechanism and presence of BAT in adult humans. Although there is ongoing work regarding the measurement of this novel tissue in humans, many challenges still need to be overcome. Furthermore, studies need to be designed to determine ways to stimulate and recruit BAT as well as to determine how effective and clinically relevant BAT thermogenesis will be in the treatment of metabolic disorders.