Endothelial/Nitric Oxide Regulation of Brown Adipose Tissue Activating Lipokine, 12, 13-diHOME and Its Antiatherogenic Actions

Abstract

Activation of brown adipose tissue (BAT) has been shown to decrease atherosclerosis due to its systemic actions to improve insulin sensitivity and facilitate weight loss. However, the direct effect of BAT cytokines on vascular arterial function and atherosclerosis has not been studied. We have reported that enhancing insulin’s action on the endothelial cells (EC) by overexpressing IRS1 to the EC on ApoE-/- background (ECIRS1/ApoE-/- mice) greatly increased insulin induced NO production and decreased atherosclerosis. ECIRS1 mice exhibited significant increases in BAT mass and activation when exposed to cold temperature (5°C), in parallel with elevation of BAT lipokine, 12,13-diHOME levels at basal, regular chow (RD) or high fat diet (HFD) compared to wild type mice (WT) by 188±33% and 187±39%, respectively, (P<0.01). Recently, 12,13 diHOME has been reported to activate BAT (Nat. Med, 2017. Elevation of 12, 13 diHOME induced by cold temperature was inhibited by L-NAME, an inhibitor of NO. In EC, the addition of 12,13-diHOME increase pAkt from 1-100nM, but without affecting peNOS and pErk. However, oxLDL-induced pErk activity and VCAM-1 expression were reduced in 12,13-diHOME (1nM) treated EC. Further, 12,13-diHOME also increased intracellular calcium concentration with parallel elevation in NO production in EC. Functionally, 12,13-diHOME(1nM-10nM) increased vascular relaxation in myography experiments significantly by 7.5%-24%. Using antibody arrays for assessing the effects of 12,13-diHOME on NO production in EC, signaling studies showed 12,13-diHOME activated mTOR, CREB and HSP27 (by 50, 2.5, and 4 fold, respectively) and down-regulated tyrosine-protein kinase (HCK) and GSK3α/β (by 30% and 26%, p<0.05) in EC. These studies for the first time showed that insulin’s action in EC can regulate BAT lipokine 12,13-diHOME expression in a positive feedback loop to increase NO and increase vasodilation with associated decrease in atherosclerosis. Disclosure K. Park: None. Q. Li: None. M. Lynes: None. H. Yokomizo: None. T. Shinjo: None. R. St-Louis: None. J. Fu: None. C. Rask-Madsen: Research Support; Self; Novo Nordisk A/S. Y. Tseng: Other Relationship; Self; Chugai Pharmaceutical Co., Ltd.. Research Support; Self; MedImmune. G.L. King: Research Support; Self; Sanofi-Aventis.