SUN-592 Adipocyte Specific Endothelin a Receptor Knockout Increases Adiposity in Mice

Obesity is associated with increased levels of Endothelin-1 (ET-1). Blockade of ET-1 type A receptors (ET(A)) improves lipid profile in patients with chronic kidney disease; however the mechanism is unknown.[1] In adipocytes ET(A) activation increases lipolysis, a potential mechanism for elevated lipids in obese individuals.[2] Therefore, the goal of this study was to determine if adipocyte specific knockout (KO) of the ET(A) receptor in mice alters genes associated with lipid metabolism in adipose and improves plasma lipids. 24-week old adipocyte ET(A) knockout mice had significantly elevated body weight compared to floxed controls (32.6±1.0 vs. 29.5±0.7 g respectively). Echo MRI revealed that the increased body weight was due to greater adiposity (10.1±0.9 vs. 14.7±1.8 % body weight; floxed vs. KO), while no statistical difference was observed in lean weight (88.9±2.4 vs. 86.8±2.6 % body weight; floxed vs. KO). Surprisingly, there were no statistical differences in plasma total cholesterol or triglycerides. RNA sequencing indicated downregulation of 597 genes and upregulation of 444 genes in visceral adipose and downregulation of 368 and upregulation of 847 genes in subcutaneous adipose. KEGG pathway analysis revealed that most genes altered in visceral adipose were related to metabolic pathways. These data implicate a role for adipose tissue ET(A) receptors in regulating adiposity and promoting pathophysiology related to obesity. 1. Farrah, T.E., et al., Endothelin Receptor Antagonism Improves Lipid Profiles and Lowers PCSK9 (Proprotein Convertase Subtilisin/Kexin Type 9) in Patients With Chronic Kidney Disease. Hypertension, 2019. 74(2): p. 323-330. 2. Eriksson, A.K., et al., Endothelin-1 stimulates human adipocyte lipolysis through the ET A receptor. Int J Obes (Lond), 2009. 33(1): p. 67-74.