Division of Endocrinology, Department of Internal Medicine, and.
Barnstable Brown Diabetes and Obesity Center, College of Medicine.
J Clin Invest. 2020 May 1;130(5):2319-2331. doi: 10.1172/JCI134892.
BACKGROUNDBeige adipose tissue is associated with improved glucose homeostasis in mice. Adipose tissue contains β3-adrenergic receptors (β3-ARs), and this study was intended to determine whether the treatment of obese, insulin-resistant humans with the β3-AR agonist mirabegron, which stimulates beige adipose formation in subcutaneous white adipose tissue (SC WAT), would induce other beneficial changes in fat and muscle and improve metabolic homeostasis.METHODSBefore and after β3-AR agonist treatment, oral glucose tolerance tests and euglycemic clamps were performed, and histochemical analysis and gene expression profiling were performed on fat and muscle biopsies. PET-CT scans quantified brown adipose tissue volume and activity, and we conducted in vitro studies with primary cultures of differentiated human adipocytes and muscle.RESULTSThe clinical effects of mirabegron treatment included improved oral glucose tolerance (P < 0.01), reduced hemoglobin A1c levels (P = 0.01), and improved insulin sensitivity (P = 0.03) and β cell function (P = 0.01). In SC WAT, mirabegron treatment stimulated lipolysis, reduced fibrotic gene expression, and increased alternatively activated macrophages. Subjects with the most SC WAT beiging showed the greatest improvement in β cell function. In skeletal muscle, mirabegron reduced triglycerides, increased the expression of PPARγ coactivator 1 α (PGC1A) (P < 0.05), and increased type I fibers (P < 0.01). Conditioned media from adipocytes treated with mirabegron stimulated muscle fiber PGC1A expression in vitro (P < 0.001).CONCLUSIONMirabegron treatment substantially improved multiple measures of glucose homeostasis in obese, insulin-resistant humans. Since β cells and skeletal muscle do not express β3-ARs, these data suggest that the beiging of SC WAT by mirabegron reduces adipose tissue dysfunction, which enhances muscle oxidative capacity and improves β cell function.TRIAL REGISTRATIONClinicaltrials.gov NCT02919176.FUNDINGNIH: DK112282, P30GM127211, DK 71349, and Clinical and Translational science Awards (CTSA) grant UL1TR001998.
米色脂肪组织与改善小鼠的葡萄糖稳态有关。脂肪组织含有β3-肾上腺素能受体（β3-ARs），本研究旨在确定β3-AR 激动剂米拉贝隆治疗肥胖、胰岛素抵抗的人类，是否会刺激皮下白色脂肪组织（SC WAT）中的米色脂肪形成，从而引起脂肪和肌肉的其他有益变化，并改善代谢稳态。
在β3-AR 激动剂治疗前后，进行口服葡萄糖耐量试验和正葡萄糖钳夹，对脂肪和肌肉活检进行组织化学分析和基因表达谱分析。PET-CT 扫描定量棕色脂肪组织体积和活性，我们进行了原代分化的人脂肪细胞和肌肉细胞的体外研究。
米拉贝隆治疗的临床效果包括改善口服葡萄糖耐量（P < 0.01）、降低糖化血红蛋白水平（P = 0.01）、改善胰岛素敏感性（P = 0.03）和β细胞功能（P = 0.01）。在 SC WAT 中，米拉贝隆治疗刺激脂肪分解，减少纤维化基因表达，并增加交替激活的巨噬细胞。具有最多 SC WAT 米色化的受试者β细胞功能改善最大。在骨骼肌中，米拉贝隆降低甘油三酯，增加过氧化物酶体增殖物激活受体γ共激活因子 1α（PGC1A）的表达（P < 0.05），并增加 I 型纤维（P < 0.01）。用米拉贝隆处理的脂肪细胞的条件培养基在体外刺激肌肉纤维 PGC1A 表达（P < 0.001）。
米拉贝隆治疗显著改善了肥胖、胰岛素抵抗的人类的多种葡萄糖稳态指标。由于β细胞和骨骼肌不表达β3-ARs，这些数据表明，米拉贝隆诱导的 SC WAT 米色化减少了脂肪组织功能障碍，从而增强了肌肉氧化能力并改善了β细胞功能。
Clinicaltrials.gov NCT02919176。
NIH：DK112282、P30GM127211、DK71349 和临床和转化科学奖（CTSA）赠款 UL1TR001998。
