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一种潜在方法。这类β3-肾上腺素能受体(AR)激动剂可以刺激啮齿动物蝙蝠，但这种活性从未在人类身上得到证实。在过去的一年里，我们发表了一些研究结果，其中我们确定了200毫克口服米拉贝格隆(Myrbetriq，Astellas Pharma，Inc.)与安慰剂相比刺激BAT的能力。米拉贝格隆是一种β3-AR激动剂，目前被批准用于治疗过度活跃的膀胱。在所有12名健康男性受试者中，通过正电子发射断层扫描结合计算机断层扫描的18F-脱氧葡萄糖测定，米拉贝格隆导致BAT代谢活性增加(p=0.001)，并使静息代谢率增加20340kcal/d(+13%；p=0.001)。BAT代谢活动也是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BAT产热，有望成为治疗代谢性疾病的有效药物。 我们最近出版了第一本人类蝙蝠地图集，BATlas 1.0。我们与孔晨合作，研究了20名健康青年男子，其中12人在耐受性冷暴露5h后，平均体重指数(BMI)为23.2 1.9 kg/m2，8人肥胖，BMI为34.8 3.3 kg/m2。用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的体积和活性。肥胖男性的活性蝙蝠比瘦男性少(平均为130mLvs.334mL.)，但在含有蝙蝠的仓库中脂肪较多(平均为1,646mLvs.855mL.)，个体之间活跃BAT与非活跃脂肪的比率范围很大(0.171%)。颈椎、锁骨上、腋窝、纵隔、脊柱旁和腹部6个解剖区域激活了BAT，其中6720%的激活BAT集中在由上躯干前三个部位组成的连续筋膜层。这些非皮下脂肪库占总体重的1.5%(占总脂肪质量的4.3%)，每个脂肪库中高达90%的脂肪可以被激活。BAT的数量和活性受到感兴趣区选择方法、PET阈值标准和PET分辨率的显著影响。目前的研究表明，在成人特定的脂肪储存库中可以发现活性BAT，但这些脂肪储存库中只有不到一半的脂肪受到急性寒冷的刺激，显示出以前被低估的生热潜力。 我们还发表了剂量反应研究的结果，其中包括与Berg Pharma合作的探索性代谢组学。我们发现，除了膀胱松弛外，人β3-AR还有助于白色脂肪组织的脂肪分解、BAT产热、胆囊松弛和胆汁酸代谢。在开发更具选择性的β3-AR激动剂来治疗肥胖相关并发症时，应该考虑这种生理学因素。 除了这些项目，我们还利用在临床试验期间收集的经过处理的血液和组织来支持我们的同事进行探索性和机械性研究。例如，曾玉华在一系列论文中表明，蝙蝠衍生的激素12，13-diHOME和12-HEPE增加组织对脂肪酸和葡萄糖的摄取，而MaR2则减少炎症。

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.