Physiological Responses to Activation of Human Brown Adipose Tissue

点击翻译按钮获取中文摘要

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.