Background: Adipocyte dysfunction links obesity to type 2 diabetes (T2D). To develop novel antidiabetic drugs, it is essential to delineate the signaling pathways that regulate adipocyte function under physiological and pathophysiological conditions. Recent studies have shown that β-arrestin-1 and -2 (barr1 and barr2, respectively), two intracellular signaling proteins known for their ability to modulate signaling via G protein-coupled receptors (GPCRs), regulate many important metabolic functions, sometimes even in a GPCR-independent fashion.
Objective: To understand the role of barr1 in adipocyte function, obesity, and whole body glucose and energy homeostasis.
Methods: To assess the role of barr1 in regulating adipocyte function, we used Cre-lox technology to generate mutant mice that lacked barr1 selectively in adipocytes(adipo-barr1-KO). These mutant mice, together with their control littermates, were subjected to a series of metabolic tests. Moreover, we used various molecular and biochemical techniques to probe the molecular mechanism through which barr1 modulates adipocyte function.
Results: We found that adipo-barr1-KO mice showed greatly impaired glucose tolerance and insulin sensitivity when consuming an obesogenic diet. In contrast, transgenic mice that overexpressed barr1 in adipocytes were protected against the metabolic deficits caused by a high-calorie diet. At the cellular level, barr1 deficiency led to a myogenic re-programming of brown adipose tissue (BAT), causing elevated plasma myostatin levels, which in turn led to impaired insulin signaling in peripheral tissues. Additional in vivo studies indicated that barr1-mediated suppression of myostatin expression by BAT is required for maintaining euglycemia.
Conclusion: Our data suggest that strategies aimed at enhancing barr1 expression or activity in BAT may prove beneficial for the treatment of T2D.
S. Pydi: None. S. Jain: None. L.F. Barella: None. J. Meister: None. L. Wang: None. Y. Cui: None. O. Gavrilova: None. J. Wess: None.
National Institute of Diabetes and Digestive and Kidney Diseases