Physiological Responses to Activation of Human Brown Adipose Tissue

通过激活内源性棕色脂肪组织（BAT）增加能量消耗是治疗肥胖和糖尿病的潜在方法。 β 3-肾上腺素能受体（AR）激动剂刺激啮齿动物BAT，但这种活性从未在人类中得到证实。 在过去的一年里，我们发表了研究结果，其中我们确定了200 mg口服米拉贝隆（Myrbetriq，Astellas Pharma，Inc.），一种β 3-AR激动剂，目前被批准用于治疗膀胱过度活动症，与安慰剂相比，刺激BAT。 在所有12名健康男性受试者中，使用正电子发射断层扫描（PET）结合计算机断层扫描（CT）通过18 F-氟脱氧葡萄糖（18 F-FDG）测量，Mirabegron导致BAT代谢活性升高（p = 0.001），静息代谢率（RMR）增加203 40 kcal/天（+13%; p = 0.001）。 BAT代谢活性也是RMR变化的重要预测因子（p = 0.006）。 因此，3-AR激动剂可以刺激人类BAT产热，并且可能是代谢疾病的有希望的治疗。 我们最近发表了人类BAT的第一个图谱，BATlas 1.0。 在与孔晨合作，我们研究了20名健康的年轻男子12瘦，平均体重指数（BMI）23.2 - 1.9 kg/m2，8肥胖，BMI 34.8 - 3.3 kg/m2后，5小时的可耐受的冷暴露。 我们通过18F标记的氟脱氧葡萄糖正电子发射断层扫描/计算机断层扫描（PET/CT）测量BAT体积和活性。肥胖男性的活化BAT比瘦人少（平均值为130与334 mL），但在含BAT的贮库中脂肪更多（平均值为1，646与855 mL），个体之间活化BAT与非活性脂肪的比例范围很宽（0.171%）。6个解剖区域激活BAT：颈部，锁骨上，腋窝，纵隔，椎旁，和abdominalwith 67 - 20%的所有激活BAT集中在一个连续的筋膜层，包括前三个仓库在上躯干。这些非皮下脂肪库占总体重的1.5%（占总脂肪量的4.3%），每个脂肪库的90%可以被激活BAT。BAT的数量和活性受到感兴趣区域选择方法、PET阈值标准和PET分辨率的显著影响。目前的研究表明，在成年人的特定脂肪库中可以发现活性BAT，但这些脂肪库中不到一半的脂肪受到急性冷暴露的刺激，这表明以前未被充分认识的产热潜力。 我们还刚刚发表了剂量反应研究的结果，其中包括与贝格制药公司合作的探索性代谢组学。 我们发现，除了膀胱松弛，人β 3-AR有助于白色脂肪组织脂解、BAT产热、胆囊松弛和胆汁酸代谢。在开发更具选择性的β 3-AR激动剂以治疗肥胖相关并发症时应考虑这种生理学。

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 just 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.