Physiological Responses to Activation of Human Brown Adipose Tissue

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Increasing energy expenditure through activation of endogenous brown adipose tissue (BAT) is a potential approach to treat obesity and diabetes. The class of beta3-adrenergic receptor (AR) agonists stimulates rodent BAT, but this activity has never been demonstrated in humans. This past year we published findings in which we determined the ability of 200 mg oral mirabegron (Myrbetriq, Astellas Pharma, Inc.), a beta3-AR agonist currently approved to treat overactive bladder, to stimulate BAT as compared to placebo. Mirabegron led to higher BAT metabolic activity as measured via 18F-fluorodeoxyglucose (18F-FDG) using positron emission tomography (PET) combined with computed tomography (CT) in all twelve healthy male subjects (p = 0.001), and it increased resting metabolic rate (RMR) by 203 40 kcal/day (+13%; p = 0.001). BAT metabolic activity was also a significant predictor of the changes in RMR (p = 0.006). Therefore, a 3-AR agonist can stimulate human BAT thermogenesis and may be a promising treatment for metabolic disease. We recently published the first atlas of human BAT, the BATlas 1.0. In collaboration with Kong Chen, we studied 20 healthy young men 12 lean, mean body mass index (BMI) 23.2 1.9 kg/m2; 8 obese, BMI 34.8 3.3 kg/m2 after 5 h of tolerable cold exposure. We measured BAT volume and activity by 18F-labeled fluorodeoxyglucose positron emission tomography/computerized tomography (PET/CT). Obese men had less activated BAT than lean men (mean, 130 vs. 334 mL) but more fat in BAT-containing depots (mean, 1,646 vs. 855 mL) with a wide range (0.171%) in the ratio of activated BAT to inactive fat between individuals. Six anatomic regions had activated BAT: cervical, supraclavicular, axillary, mediastinal, paraspinal, and abdominalwith 67 20% of all activated BAT concentrated in a continuous fascial layer comprising the first three depots in the upper torso. These nonsubcutaneous fat depots amounted to 1.5% of total body mass (4.3% of total fat mass), and up to 90% of each depot could be activated BAT. The amount and activity of BAT was significantly influenced by region of interest selection methods, PET threshold criteria, and PET resolutions. The present study suggests that active BAT can be found in specific adipose depots in adult humans, but less than one-half of the fat in these depots is stimulated by acute cold exposure, demonstrating a previously underappreciated thermogenic potential. We also published the results of the dose response study in which we included exploratory metabolomics in collaboration with BERG Pharma. We showed that besides urinary bladder relaxation, the human beta3-AR contributes to white adipose tissue lipolysis, BAT thermogenesis, gallbladder relaxation, and bile acid metabolism. This physiology should be considered in the development of more selective beta3-AR agonists to treat obesity-related complications. Beyond these projects, we are utilizing the curated blood and tissue collected during our clinical trials to support exploratory and mechanistic studies by our colleagues. For example, Yu-Hua Tseng has shown in a series of papers that the BAT-derived hormones 12,13-diHOME and 12-HEPE increase tissue uptake of fatty acids and glucose, while MaR2 reduces inflammation.