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-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。 此外，我们最近描述了一种新的非侵入性和非电离成像方法，以评估蝙蝠在小鼠使用对比增强超声（CEUS）。在过去的一年里，我们报告了这种方法在健康人体中的应用。 招募了13名健康志愿者。在所有受试者冷暴露之前和之后，使用连续静脉输注充有perflutren气体的脂质微泡和锁骨上间隙的触发成像进行CEUS。前5名受试者以低于随后8名受试者的输注速率接受微泡，并作为一个单独的组进行分析。血流量估计为微泡补充曲线的平台（A）和斜率（）的乘积。冷暴露后行18F-FDG PET/CT检查。 在所有受试者中，随着触发间隔的增加，锁骨上脂肪组织区域的声信号增加，表明存在血流。CEUS成像的区域与BAT共定位，如18F-FDG PET/CT所检测。在采用优化CEUS方案的8名受试者的队列中，与温暖条件下的基础BAT血流相比，CEUS衍生的BAT血流随着冷暴露而增加（中位数A = 3.3 Au/s四分位距，0.5-5.7 Au/s vs 1.25 Au/s四分位距，0.5-2.6 Au/s; P = 0.02）。在这8名受试者中，5名受试者在冷暴露后血流量增加了两倍以上;这些反应者通过18F-FDG PET/CT测量的BAT活性更高（中位最大标准化摄取值，2.25四分位距，1.53-4.57 vs 0.51四分位距，0.47-0.73; P = 0.02）。 因此，CEUS作为一种非侵入性、非电离成像方式在估计年轻健康人的BAT血流方面是可行的。CEUS可能是评估BAT和BAT靶向治疗的有用和可扩展的工具。

Increasing energy expenditure through activation of endogenous brown adipose tissue (BAT) is a potential approach to treat obesity and diabetes. The class of β3-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 β3-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 β3-AR agonist can stimulate human BAT thermogenesis and may be a promising treatment for metabolic disease. In addition, we recently described a novel noninvasive and nonionizing imaging method to assess BAT in mice using contrast-enhanced ultrasound (CEUS). This past year, we reported application of this method in healthy humans. Thirteen healthy volunteers were recruited. CEUS was performed before and after cold exposure in all subjects using a continuous intravenous infusion of perflutren gas-filled lipid microbubbles and triggered imaging of the supraclavicular space. The first five subjects received microbubbles at a lower infusion rate than the subsequent eight subjects and were analyzed as a separate group. Blood flow was estimated as the product of the plateau (A) and the slope (β) of microbubble replenishment curves. All underwent 18F-FDG PET/CT after cold exposure. An increase in the acoustic signal was noted in the supraclavicular adipose tissue area with increasing triggering intervals in all subjects, demonstrating the presence of blood flow. The area imaged by CEUS colocalized with BAT, as detected by 18F-FDG PET/CT. In a cohort of eight subjects with an optimized CEUS protocol, CEUS-derived BAT blood flow increased with cold exposure compared with basal BAT blood flow in warm conditions (median Aβ = 3.3 AU/s interquartile range, 0.5-5.7 AU/s vs 1.25 AU/s interquartile range, 0.5-2.6 AU/s; P = .02). Of these eight subjects, five had greater than twofold increases in blood flow after cold exposure; these responders had higher BAT activity measured by 18F-FDG PET/CT (median maximal standardized uptake value, 2.25 interquartile range, 1.53-4.57 vs 0.51 interquartile range, 0.47-0.73; P = .02). Therefore, CEUS is feasible as a noninvasive, nonionizing imaging modality in estimating BAT blood flow in young, healthy humans. CEUS may be a useful and scalable tool in the assessment of BAT and BAT-targeted therapies.