Regulation of adipose thermogenesis by Epidermal Growth Factor and angiotensin AT2 receptor activation

Abstract

Transgenic “sRA” mice with hyperactivity of the brain renin‐angiotensin system (RAS) express human renin via the synapsin promoter and human angiotensinogen via its own promoter. sRA mice exhibit increased resting metabolic rate (RMR) due to reduced activation of adipose angiotensin AT2 receptors. To identify downstream pathways, RNA‐Seq was performed using inguinal adipose from sRA and littermate controls, with or without infusion of the AT2 agonist CGP‐42112a (“CGP,” 50 ng/kg/min, s.c.). In sRA vs controls, there were significant expression changes in 123 genes, which were mostly normalized by CGP. 51 of these genes are associated with epidermal growth factor (EGF). To determine the sufficiency of EGF to increase RMR, male C57Bl/6J mice were infused with EGF (0.8 ug/hr, 2 weeks, n=8) or saline (n=9), resulting in increased RMR (+38±12 cal/hr vs control, P=0.006), and a trend toward reduced inguinal (176±21 vs 140±17 mg P=0.20) and increased brown (54±6 vs 68±4 mg, P=0.08) adipose. Co‐infusion of CGP (n=5) caused trends toward ameliorated RMR (+15±22 cal/hr vs control, P=0.31 vs control, P=0.13 vs EGF) and inguinal adipose (187±21 mg, P=0.15 vs EGF). Ongoing studies are aimed at optimizing doses of EGF and CGP in C57Bl/6J mice, and at quantifying EGF and evaluating the effects of chronic EGF blockade in sRA mice. Together these data support a role for EGF, and modulation of EGF signaling by AT2 receptors, in RMR control.