Adipocyte-Selective Deletion of ß-Arrestin-1 in Mice Causes Adiposity, Impaired Glucose Tolerance, and Reduced Insulin Sensitivity

Abstract

In obese individuals, excess fat accumulates in adipose tissue (AT), leading to altered AT metabolism and increased insulin resistance, a key feature of type 2 diabetes (T2D). Therefore, it is of great importance to understand the signaling pathways that regulate AT function. Activation of certain G protein-coupled receptors (GPCRs) in AT has been reported to have beneficial effects on whole body glucose homeostasis. GPCR signaling is modulated by β-arrestin-1 and -2 (barr1 and barr2, respectively), two intracellular proteins which can terminate GPCR signaling and/or mediate G protein-independent signaling. The two β-arrestins are known to regulate many important physiological functions, primarily based on work with whole body knockout (KO) mice. The potential roles of barr1 and barr2 in regulating adipocyte function in vivo remain unexplored. To address this issue, we used Cre-lox technology to generate mutant mice that lacked barr1 selectively in adipocytes (adipo-barr1 KO mice). Interestingly, adipo-barr1 KO mice maintained on a high-fat diet showed significantly increased body weight and adiposity, impaired glucose tolerance, and reduced insulin sensitivity. Moreover, blood glucose and plasma insulin levels were elevated in adipo-barr1 KO mice, indicative of peripheral insulin resistance. RNA-seq analysis revealed the down regulation of key genes involved in glycolysis, glycogen synthesis and insulin signaling. More detailed studies into the mechanisms through which barr1 regulates adipocyte function may identify novel signaling pathways that can be targeted for therapeutic purposes. Disclosure S. Pydi: None. J. Wess: None.