The interest in brown adipose tissue (BAT) as a target to combat metabolic disease has recently been renewed with the discovery of functional BAT in humans. In rodents, BAT can be activated by bile acids, which activate type 2 iodothyronine deiodinase (D2) in BAT via the G-coupled protein receptor TGR5, resulting in increased oxygen consumption and energy expenditure. Here we examined the effects of oral supplementation of the bile acid chenodeoxycholic acid (CDCA) on human BAT activity. Treatment of 12 healthy female subjects with CDCA for 2 days resulted in increased BAT activity. Whole-body energy expenditure was also increased upon CDCA treatment. In vitro treatment of primary human brown adipocytes derived with CDCA or specific TGR5 agonists increased mitochondrial uncoupling and D2 expression, an effect that was absent in human primary white adipocytes. These findings identify bile acids as a target to activate BAT in humans.

These results indicate that chronic endurance exercise is not associated with brown and beige adipocyte recruitment; in fact endurance training appears to be linked to lower the metabolic activity of BAT in humans.

The obesity pandemic has spurred a need for novel therapies to prevent and treat metabolic complications. The recent rediscovery of brown adipose tissue (BAT) in humans made this tissue a possible therapeutic target, due to its potentially substantial contributions to energy homeostasis. Fibroblast growth factor 21 (FGF21) has been identified as a facilitator of cold-induced thermogenesis in humans. Furthermore, pre-clinical studies revealed that FGF21 administration leads to improvement in the metabolic consequences of obesity, such as dyslipidemia and type 2 diabetes. Here we studied plasma FGF21 levels in two cohorts of human subjects, in whom BAT activity was determined using an individualized cooling protocol by [18F]FDG-PET/CT scan. Importantly, we found that circulating FGF21 levels correlated with BAT activity during acute cold exposure in male subjects. In addition, FGF21 levels were related to the change in core temperature upon acute cold exposure, indicating a role for FGF21 in maintaining normothermia, possibly via activation of BAT. Furthermore, cold acclimation increased BAT activity in parallel with increased FGF21 levels. In conclusion, our results demonstrate that FGF21 levels in humans are related to BAT activity, suggesting that FGF21 may represent a novel mechanism via which BAT activity in humans may be enhanced.

Background/ObjectivesThyroid hormone receptors are present on brown adipose tissue (BAT), indicating a role for thyroid hormone in the regulation of BAT activation. The objective of this study was to examine the effect of thyroid hormone withdrawal followed by thyroid hormone in TSH-suppressive dosages, on energy expenditure and brown adipose tissue activity.Subjects/MethodsThis study was a longitudinal study in an academic center, with a follow-up period of 6 months. Ten patients with well-differentiated thyroid carcinoma eligible for surgical treatment and subsequent radioactive iodine ablation therapy were studied in a hypothyroid state after thyroidectomy and in a subclinical hyperthyroid state (TSH-suppression according to treatment protocol). Paired two-tailed t-tests and linear regression analyses were used.ResultsBasal metabolic rate (BMR) was significantly higher after treatment with synthetic thyroid hormone (levothyroxine) than in the hypothyroid state (BMR 3.8 ± 0.5 kJ/min versus 4.4 ± 0.6 kJ/min, P = 0.012), and non-shivering thermogenesis (NST) significantly increased from 15 ± 10% to 25 ± 6% (P = 0.009). Mean BAT activity was significantly higher in the subclinical hyperthyroid state than in the hypothyroid state (BAT standard uptake value (SUVMean) 4.0 ± 2.9 versus 2.4 ± 1.8, P = 0.039).ConclusionsOur study shows that higher levels of thyroid hormone are associated with a higher level of cold-activated BAT.Trial RegistrationClinicalTrials.gov NCT02499471