Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, NIH-20892, USA.
Mouse Metabolism Core, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 20892, USA.
Nat Commun. 2019 Jul 3;10(1):2936. doi: 10.1038/s41467-019-11003-4.
β-Arrestins are major regulators of G protein-coupled receptor-mediated signaling processes. Their potential roles in regulating adipocyte function in vivo remain unexplored. Here we report the novel finding that mice lacking β-arrestin-2 (barr2) selectively in adipocytes show significantly reduced adiposity and striking metabolic improvements when consuming excess calories. We demonstrate that these beneficial metabolic effects are due to enhanced signaling through adipocyte β3-adrenergic receptors (β3-ARs), indicating that barr2 represents a potent negative regulator of adipocyte β3-AR activity in vivo. Interestingly, essentially all beneficial metabolic effects caused by adipocyte barr2 deficiency are absent in adipocyte barr2-PRDM16 double KO mice, indicating that the metabolic improvements caused by the lack of barr2 in adipocytes are mediated by the browning/beiging of white adipose tissue. Our data support the novel concept that 'G protein-biased' β3-AR agonists that do not promote β3-AR/barr2 interactions may prove useful for the treatment of obesity and related metabolic disorders.
β-arrestins 是 G 蛋白偶联受体介导的信号转导过程的主要调节剂。它们在调节体内脂肪细胞功能方面的潜在作用仍未被探索。在这里，我们报告了一个新的发现，即脂肪细胞特异性缺乏β-arrestin-2（barr2）的小鼠在摄入过量卡路里时表现出明显的肥胖减轻和显著的代谢改善。我们证明，这些有益的代谢效应是由于通过脂肪细胞β3-肾上腺素能受体（β3-AR）增强信号转导所致，表明 barr2 代表体内脂肪细胞β3-AR 活性的有效负调节剂。有趣的是，脂肪细胞 barr2 缺陷引起的所有有益代谢效应在脂肪细胞 barr2-PRDM16 双重 KO 小鼠中均不存在，表明脂肪细胞 barr2 缺失引起的代谢改善是由白色脂肪组织的褐变/米色化介导的。我们的数据支持了一个新的概念，即“偏向 G 蛋白”的β3-AR 激动剂，不促进β3-AR/barr2 相互作用，可能对肥胖症和相关代谢紊乱的治疗有用。
