Physiological Responses to Activation of Human Brown Adipose Tissue

对人类棕色脂肪组织激活的生理反应

• 批准号: 9148970
• 负责人: Aaron Cypess
• 金额: $ 10.37万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9148970
• 关键词: Acoustics; Adipose tissue; Adrenergic Agonists; Adrenergic Receptor; Adverse effects; Advisory Committees; Area; Basal metabolic rate; Binding; Blood flow; Brown Fat; Cardiovascular system; Chronic; Continuous Intravenous Infusion; Diabetes Mellitus; Diastolic blood pressure; Dose; Effectiveness; Energy Metabolism; FDA approved; Future; Gases; Hour; Human; Image; Infusion procedures; Label; Lipids; Measures; Metabolic; Metabolic Diseases; Methods; Microbubbles; Mus; Obesity; Oral; Overactive Bladder; Pharmaceutical Preparations; Phase; Physiological; Pilot Projects; Placebos; Positron-Emission Tomography; Protocols documentation; Publishing; Recruitment Activity; Reporting; Reproductive Health; Rodent; Signal Transduction; Supraclavicular; Thermogenesis; Time; Ultrasonography; X-Ray Computed Tomography; clinically relevant; cohort; contrast enhanced; dosage; experience; fluorodeoxyglucose; fluorodeoxyglucose positron emission tomography; healthy volunteer; imaging modality; male; meetings; men; novel; response; targeted treatment; tool; uptake

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.

通过激活内源性棕色脂肪组织（BAT）来增加能量消耗是一种治疗肥胖症和糖尿病的潜在方法。 β3-肾上腺素能受体（AR）激动剂刺激了啮齿动物的蝙蝠，但是这种活性在人类中从未得到证明。 在过去的一年中，我们发表了研究结果，在这些发现中，我们确定了200 mg口服mirabegron（Myrbetriq，Astellas Pharma，Inc。），这是一种目前批准治疗过度活跃膀胱的β3-AR激动剂与安慰剂相比刺激蝙蝠。 Mirabegron通过正电子发射断层扫描（PET）与18F氟脱氧葡萄糖（18F-FDG）进行了较高的BAT代谢活性，并在所有十二个健康的男性受试者（P = 0.001）中结合了计算机断层扫描（CT）（PET）（P = 0.001），并将静止的代谢率（RMR）提高到203 40 kcal/kcal day（+13％）。 BAT代谢活性也是RMR变化的重要预测指标（P = 0.006）。 因此，β3-ar激动剂可以刺激人类蝙蝠的生热发生，并且可能是代谢疾病的有前途的治疗方法。 此外，我们最近描述了一种新型的非侵入性和非离子成像方法，用于使用对比增强超声（CEU）评估小鼠的蝙蝠。在过去的一年中，我们报告了这种方法在健康人类中的应用。 招募了13名健康志愿者。在所有受试者的冷暴露之前和之后，使用持续静脉注射纯净脂质脂质微泡和触发上锁骨上空间的成像进行了冷接触之前和之后进行CEU。前五名受试者的输注率低于随后的八名受试者，并作为单独的组进行了分析。血流估计为高原（A）和微泡补充曲线的斜率（β）的乘积。冷暴露后，所有均接受了18F-FDG PET/CT。 在锁骨上脂肪组织区域中，声学信号的增加随着所有受试者的触发间隔的增加，表明血液流动的存在。由CEU成像的区域与BAT共定位，如18F-FDG PET/CT所检测到的。在八个具有优化CEUS方案的受试者组成的队列中，与基础蝙蝠血流相比，在温暖条件下，CEUS衍生的蝙蝠血流增加了（中位Aβ= 3.3aβ= 3.3 AU/s的四分之一四分位数，0.5-5.7 au/s vs 1.25 au/s Q.125 au/s Quartile范围，Quartile范围为0.5-2.6 au/s; p = .02）。在这八名受试者中，五名受试者在冷暴露后血流增加了两倍以上。这些响应者的BAT活性较高，通过18F-FDG PET/CT（中值最大标准化吸收值，2.25四分位间距范围，1.53-4.57 vs 0.51零心间范围，0.47-0.73; p = .02）。 因此，在估计年轻，健康人的蝙蝠血流时，CEU是一种无创，非离子成像方式的可行性。 CEUS可能是评估BAT和靶向BAT靶向疗法的有用且可扩展的工具。