Adipocyte β-arrestin-2 is essential for maintaining whole body glucose and energy homeostasis

Sai P. Pydi, Shanu Jain, Wesley Tung, Yinghong Cui, Lu Zhu, Wataru Sakamoto, Shalini Jain, Brent S. Abel, Monica C. Skarulis, Jie Liu, Thanh Huynh, Karel Pacak, Marc G. Caron, Oksana Gavrilova, Toren Finkel and Jürgen Wess ()
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Sai P. Pydi: National Institute of Diabetes and Digestive and Kidney Diseases
Shanu Jain: National Institute of Diabetes and Digestive and Kidney Diseases
Wesley Tung: National Institute of Diabetes and Digestive and Kidney Diseases
Yinghong Cui: National Institute of Diabetes and Digestive and Kidney Diseases
Lu Zhu: National Institute of Diabetes and Digestive and Kidney Diseases
Wataru Sakamoto: National Institute of Diabetes and Digestive and Kidney Diseases
Shalini Jain: National Institute of Diabetes and Digestive and Kidney Diseases
Brent S. Abel: National Institute of Diabetes and Digestive and Kidney Diseases
Monica C. Skarulis: National Institute of Diabetes and Digestive and Kidney Diseases
Jie Liu: National Heart, Lung, and Blood Institute
Thanh Huynh: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Karel Pacak: Eunice Kennedy Shriver National Institute of Child Health and Human Development
Marc G. Caron: Duke University Medical Center
Oksana Gavrilova: National Institute of Diabetes and Digestive and Kidney Diseases
Toren Finkel: National Heart, Lung, and Blood Institute
Jürgen Wess: National Institute of Diabetes and Digestive and Kidney Diseases

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: Abstract 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.

Date: 2019
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DOI: 10.1038/s41467-019-11003-4

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