beta-arrestin-1 in AgRP Neurons Plays Crucial Role in Maintaining Whole Body Glucose Homeostasis

Hunger and satiety are regulated, to a major extent, by the agouti-related protein (AgRP)/neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons residing in the arcuate nucleus of the hypothalamus. During starvation, AgRP neurons are strongly activated to promote hunger. Peripheral hormones and nutrients regulate the function of AgRP neurons, thus ensuring proper glucose and energy homeostasis. Recent studies from various labs, including our group, have shown the importance of G-protein coupled receptors (GPCRs) in regulating the activity of AgRP neurons. GPCR function is modulated by a pair of proteins known as beta-arrestin-1 and -2 (barr1 and barr2, respectively), which can terminate GPCR signaling and/or mediate GPCR-independent signaling. It is well established that barr1 and barr2 are involved in many important physiological functions. However, the potential roles of barr1 and barr2 in regulating the activity of AgRP neurons remain unexplored. To address this issue, we generated mice that lacked barr1 or barr2 selectively in AgRP neurons using Cre/loxP-flex-switch technology. Interestingly, AgRP-barr1-KO mice consuming a high fat diet showed significantly impaired glucose tolerance, decreased insulin sensitivity, and elevated plasma glucose and insulin levels. AgRP-barr1-KO mice did not differ from their control littermates in body weight and food intake. More detailed studies into the mechanisms through which barr1 regulates the activity of AgRP neurons may lead to new strategies to alter the activity of AgRP neurons for therapeutic purposes. Disclosure S. Pydi: None. Z. Cui: None. L.F. Barella: None. Y. Cui: None. W. Chen: None. O. Gavrilova: None. J. Wess: None.