Is activation of human brown adipose tissue a viable target for weight management?

Abstract

To date, human studies show that brown adipose tissue (BAT) contributes a small yet highly variable amount to overall energy expenditure. No studies have shown a decrease in body weight with cold-induced BAT activation, and existing pharmacological studies suggest that BAT activation via the sympathetic nervous system may result in increased heart rate and systolic blood pressure. Furthermore, even though the amount and/or activity of BAT have been shown to vary with seasons, such variation does not seem to be translated into weight changes. Collectively, these findings do not support the use of BAT activation for weight loss in humans; however, the potential role of BAT in counteracting the metabolic adaptation observed with weight loss is suggested. Although the role of BAT in weight control is currently unsubstantiated, BAT may play a role in improving insulin sensitivity in humans.

INTRODUCTION

We are facing a worldwide epidemic of obesity driven by a chronic imbalance between energy intake and expenditure. As a result, the discovery of new strategies to induce weight loss and/or improve weight loss maintenance is of upmost importance. The rediscovery of brown adipose tissue (BAT) in adults almost a decade ago (10, 20, 23, 31, 38) triggered a resurgence in BAT research as a potential avenue to curb obesity. Beyond the natural role of BAT in maintaining body temperature via heat production (i.e., nonshivering thermogenesis), induction and activation of BAT or “beiging” of white adipose tissue (WAT) reemerged as a potential means to enhance adaptive thermogenesis, increase energy expenditure, and improve weight control (35). Indeed, there are several physiological, pharmacological, even pathological factors that can impact the amount and activity of BAT (Fig. 1). Despite BAT mass having an inverse relationship with BMI (and adiposity) and age, and being lower in males (10, 20), BAT amount and activity are highly variable between studies and individuals (34–913 g among studies; Table 1). Furthermore, careful consideration must be given when one is comparing the role of BAT in rodents and humans. Whereas rodents rely heavily on BAT to stimulate thermogenesis due to a high surface-to-volume ratio, humans rely much more on muscle (compared with adipose tissue) to generate heat via macronutrient oxidation. Additionally, despite extensive studies in rodents supporting the role of BAT in cold-induced thermogenesis (CIT) and potentially in dietary-induced thermogenesis (DIT), so far, studies in humans do not support the hypothesis that induction and activation of BAT may be an effective strategy for body weight control. Despite an earlier report describing a relationship between the magnitude of cold-induced and overfeeding-induced thermogenesis (40), our recent data in humans suggest a dissociation between the regulatory mechanisms for CIT and DIT, providing some skepticism on a potential common origin (BAT activation) to both forms of thermogenesis (27).

Fig. 1.

Mediators of brown adipose tissue (BAT; or Beige) amount/activity and impact on cardiometabolic health. WAT, white adipose tissue. +, The defined mediator is positively associated with BAT (or Beige) amount/activity; −, a negative association; ?, a debatable association.

Table 1.

Estimated maximum energy expenditure by cold stimulation from human BAT

References	Subject Characteristics	Amount of Activated BAT, g	Stimulated Metabolism (Substrate Uptake/O2 Uptake)	Maximal BAT Contribution to EE, kcal/day
Mike Stock (personal communication)‡		50 g	100 × V̇o2	100 kcal/day [supported by Rothwell & Stock, 1983 (30)]
Muzik et al., 2013 (22)*	Healthy adults (n = 9; 1 M, 8 F)	Mean: 59 ± 18 g	Blood flow (high-BAT group):	5.6 kcal/day
	Age: 29.6 ± 5.5 yr	(High BAT group)	Cold: 12.9 ± 4.1 ml·100 g−1·min−1
	BMI: 22.1 ± 3.1 kg/m2
Din et al., 2016 (36)*	Healthy adults (n = 7; 5 M, 2 F) with NGT	Mean: 133 ± 59 g	Blood flow: Cold: 10.0 ± 2.4 ml·100 g−1·min−1	10 kcal/day
	Age: 36 ± 11 yr
	BMI: 25.5 ± 3.3 kg/m2
Orava et al., 2011 (24)†	Healthy adults (n = 27; 7 M, 20 F) with NGT	34 ± 22 g	FDG-glucose uptake: Cold: 9.1 ± 5.1 µmol·100 g−1·min−1 (only from 19 of 27 subjects)	33 kcal/day
	Age: 40.2 ± 9.4 yr
	BMI: 22.8 ± 2.2 kg/m2
Blondin et al., 2015 (6)†	Healthy, nonacclimated men (n = 12)	57 ± 16 g	FDG-glucose uptake:	73 kcal/day
	Age: 24 ± 1 y		Cold: 12 ± 8 µmol·100 g−1·min−1
	BMI: 25.5 ± 0.8 kg/m2
Virtanen et al., 2009 (38)†	Healthy adults (n = 5)	63 g	FDG-glucose uptake:	82 kcal/day
	Age Range: 20–50 y (inclusion)		Cold: 12.2 µmol·100 g−1·min−1
Ouellet et al., 2012 (26)†	Healthy men (n = 6)	168 ± 56 g	FDG-glucose uptake:	193 kcal/day
	Age Range: 23–42 y		Cold: 10.8 ± 4.5 µmol·100 g−1·min−1
	BMI Range: 23.7–31.0 kg/m2
van der Lans et al., 2013 (17)†	Healthy adults (n = 17; 8 M, 9 F)	913 ± 458 g	FDG-glucose uptake:	737 kcal/day
	Age: 23.0 ± 3.2 yr		Cold: 7.6 ± 2.5 µmol·100 g−1·min−1
	BMI: 21.6 ± 2.2 kg/m2

Where indicated, values are means ± SE. NGT, normal glucose tolerance. BAT, brown adipose tissue; EE, energy expenditure; FDG, fluorodeoxyglucose; BMI, body mass index.

^‡Discussion between E. Ravussin and late M. Stock: coefficient of fat mass (FM) as a determinant of RMR is 10 kcal/day/kg FM; “Resting” energy expenditure of BAT is double that of WAT (20 kcal/day/kg); BAT metabolism can be stimulated 100 times by adrenergic/cold stimulation.

^*Blood flow calculations include the assumptions that 1) O₂ content is 21.3 ml O₂/100 ml arterial blood; 2) O₂ extraction 51% or 59% by BAT; and 3) 4.72 kcal/liter O₂ for mix of 10% carbohydrate and 90% fat.

^†FDG-glucose uptake calculations include the assumptions that 1) glucose energy content 4.1 kcal/g, and 2) glucose is only 10% of BAT substrate oxidation, the remaining coming from fat oxidation.

NO IMPACT ON BODY WEIGHT IN HUMANS

To date, cold-stimulated BAT activation does not appear to elicit any meaningful decreases in body weight, but a recent study provided some evidence of small fat mass loss associated with small increases in energy expenditure (42). Unfortunately, and probably due to a lack of standardization of cold exposure experimental design in human studies, the effects of cold exposure on BAT activation, thermogenesis, and potential weight loss have been inconclusive (8, 13, 14, 19). As a result, these results are often disappointing in providing evidence for targeting BAT for weight management and potentially for obesity treatment. Potential reasons for these inconclusive results may be the lack of standardization between protocols, BAT measurement techniques, and type of intervention, as well as the method by which BAT contribution is measured and calculated. Additionally, while longer or more severe bouts of cold exposure may elicit greater BAT activation, there may be a compensatory increase in appetite and food intake, thereby potentially rendering BAT activation ineffective for managing obesity (7, 29). If BAT could serve as a target for increasing energy expenditure, it is very likely that appetite suppressant drugs along with BAT activation might help curb this potential offset caused by a compensatory increase in energy intake.

Furthermore, the relevance of BAT to whole body energy expenditure is further relegated when one acknowledges both a lesser amount of BAT and probably less active BAT in individuals who are overweight or obese (10, 14, 20), as well as the observed blunted BAT metabolic response to both cold and insulin stimulation in the presence of obesity (25). A recent perspective (16) also suggests that important relationships between energy expenditure and oxygen delivery have been ignored; however, among individuals with high BAT blood flow (25 ml·100 g tissue⁻¹·min⁻¹) to the supraclavicular region and with an estimated 100 g of total BAT (24), the calculated BAT thermogenesis was very marginal under acute cold exposure. A meticulous study by Blondin et al. (6) further suggests that the bulk of glucose turnover during cold exposure is mediated by skeletal muscle metabolic activation even when shivering is minimized, suggesting a larger role for muscle rather than BAT in the response to cold exposure. Indeed, the contribution of BAT stimulation to energy expenditure is based on the assumption that muscle activation via shivering (i.e., muscle contraction) is absent but muscle tone may be increased (44). Most assumptions that shivering does not occur during extremely mild cold exposure have been based on observation or self-report, when indeed electromyographic (EMG) data confirm that shivering in the deep and superficial muscles is present. Importantly, despite advanced imaging methods to assess BAT metabolic rate, the inability to parse out the distinct contribution of BAT activation from muscle shivering to heat production measured by indirect calorimetry still remains.

Recent data from our group further indicate that BAT does not appear to mediate the metabolic adaptation observed following 8 wk of overfeeding and weight gain in nonobese men (28). Together, the above-mentioned studies and the limited values of estimated maximum energy expenditure contribution from human BAT [i.e., 5–193 kcal/day with one exception (14, 17); Table 1] should significantly curb our enthusiasm about the role of BAT in promoting increased energy expenditure and be a potential pharmacological target for weight loss management. Furthermore, people with obesity have fewer amounts of (active) BAT than lean individuals (10, 14, 20). Interestingly, these studies showcase an approximate 1 kcal/day contribution for each gram of BAT. Importantly, the fluorodeoxyglucose (FDG)-glucose uptake estimates in Table 1 represent only the capacity of BAT to take up glucose under acute and tolerable cold conditions, which can be metabolized, stored, and/or converted to lipid; thus, it is not a direct measure of BAT metabolic rate. Labeled lipid tracer [¹¹C]acetate and [¹⁵O]H₂O for blood flow in the BAT regions, and molecular [¹⁵O]O₂ have also been used to estimate oxidative metabolism more directly. However, because of their shorter half-lives and the fact that they require dynamic scans in more restricted region(s) of interest (upper cervical and supraclavicular areas only), it is hard to assess the whole body CIT effect from longer cold exposure using these techniques. To our knowledge, no one has shown comparability among these different tracers. Some studies have shown that BAT volume (19) and oxidative capacity (5) can increase with chronic cold stimulation, thus providing more thermogenic capacity to BAT. Additionally, since BAT is also located in white adipose tissue (beige or BRITE adipocytes), our energy expenditure estimates may be somewhat low. Finally, muscle activation (i.e., muscle tone) without contraction is an important part of energy expenditure. Nonetheless, any observed or self-reported absence of shivering is not supported by EMG or PET/CT measurements, which consistently show muscle activation even during mild cold exposure.

ABSENCE OF A SEASONAL EFFECT IN HUMANS

Compared with rodents, maximally activating BAT in humans (by lowering ambient temperatures or by pharmacological agents) to stimulate energy expenditure may be impractical over extended periods of time, since it would probably lead to compensatory increases in appetite and food intake (7, 29). If BAT activation by cold exposure were important in weight control, we would expect a seasonal variation in body weight with weight loss during winter months. Nonetheless, epidemiological data do not support such weight cycling over the year and do not show true obesity gradients tracking average yearly temperatures (34). Indeed, when obesity prevalence is corrected for poverty and race, the significant negative relationship to temperature does not exist. Additionally, even if cold exposure could facilitate weight loss, humans naturally want to be in the best thermoneutral environment and therefore dress (or shed clothes) appropriately when cold or warm. Furthermore, since obese individuals are able to more effectively maintain core temperature and have less of an elevation in metabolic rate in the face of cold exposure (1), this would even lessen the impact of BAT activation on weight loss in people with obesity.

INCREASED CARDIOVASCULAR RISK WITH PHARMACOLOGICAL INTERVENTIONS

While long-term studies in humans are needed to identify the potential risks and benefits of pharmacologic interventions targeted at BAT induction and activation, pharmacological agents to date (such as β₃-adrenoreceptor agonists) have failed in clinical trials due to cardiovascular and muscular undesired effects (2, 9). Indeed, prolonged stimulation of the sympathetic nervous system to fully activate BAT is not practical because of the observed increases in heart rate and systolic blood pressure due to off-target binding of β₁- and β₂-adrenoreceptors (11). While more research is needed to develop very selective β₃-adrenorecptor agonists and to verify the safety of BAT activation via pharmacotherapy, the current state of science does not support the use of sympathomimetic molecules for activation of BAT. Although the potential thermogenic effect of capsinoids has also been explored, no changes in body weight or fat mass have been observed alongside its disputed effect on energy expenditure (12, 32, 39, 41).

POTENTIAL BAT CONTRIBUTIONS TO OVERALL HEALTH

Despite the lack of human research to support the use of BAT activation to induce weight loss and combat obesity, there are noteworthy observations of improved glucose metabolism and insulin sensitivity in humans (6, 8, 10, 13, 17, 19–21, 24, 26, 31, 37, 38, 42, 43) as well as other cardioprotective effects, such as increased triglyceride clearance, reduced hypercholesterolemia, and protection from atherosclerosis development (3, 4, 15, 18, 33). Specifically, these human studies have shown improved glucose uptake, whole body glucose disposal, and insulin sensitivity in activated BAT and cold-induced BAT. One study in healthy humans using indirect calorimetry and stable isotopes showed that cold exposure resulted in an increase in resting metabolic rate of 14% in subjects who had detectable BAT levels and that this increase was fueled by both plasma-derived glucose (30%) and free fatty acid oxidation (70%) (8).

Although the relatively small contribution of fully-activated BAT to whole body energy expenditure on average does not make it a viable target for weight loss, even a 100 kcal/day contribution gives it a potential role in weight loss maintenance by potentially counteracting some of the metabolic adaptation induced by weight loss (Fig. 2). Specifically, there is a natural trajectory for weight regain following a period of successful weight loss. Interjecting a thermogenic drug that activates BAT following weight loss may be beneficial for weight loss maintenance. More research should focus on the overall impact of BAT on cardioprotective effects and the use of BAT stimulation to promote weight loss maintenance. Additionally, BAT activation may be more efficacious in those individuals with larger BAT content.

Fig. 2.

Potential paradigm for human brown adipose tissue (BAT) to modulate weight loss maintenance.

CONCLUSION

Despite the excitement surrounding BAT induction and activation, current research in humans does not support the use of BAT activation to combat obesity or induce weight loss. While there remains a potential for BAT induction and activation to produce some cardioprotective effects, prolonged cold exposure in humans is not realistic as a strategy for weight control, mostly due to the average low estimates of BAT contribution to whole body energy expenditure. However, the highly variable size of BAT may still make it a potential target if we had easy biomarkers of it size to identify potential “responders.”

DISCLOSURES

No conflicts of interest, financial or otherwise, are declared by the authors.

AUTHOR CONTRIBUTIONS

K.L.M. and E.R. conceived and designed research; K.L.M., K.Y.C., and E.R. prepared figures; K.L.M., K.Y.C., and E.R. drafted manuscript; K.L.M., K.Y.C., and E.R. edited and revised manuscript; K.L.M., K.Y.C., and E.R. approved final version of manuscript.