Abstract P073: Chemerin Receptor Antagonism Improves Vascular Insulin Signaling in Diabetic Mice

Abstract

Adipose tissue releases many adipokines, including chemerin, which produces its effects through activation of chemokine-like receptor 1 (ChemR23). Chemerin influences major aspects of the metabolic syndrome, including adipogenesis and insulin sensitivity in adipocytes and skeletal muscle cells. Considering that chemerin impairs vascular reactivity and that amongst its many actions, insulin also influences vascular function, we postulate that chemerin decreases insulin-induced vasodilatation, by reducing PI3K/Akt signaling, and impairs glucose uptake by vascular smooth muscle cells (VSMC). Mesenteric arteries, endothelial cells (EC) or VSMC from C57Bl6 mice were incubated with chemerin (0.5 ng/mL, 1 h) or vehicle (veh). Chemerin decreased insulin-induced relaxation (0.1 - 3000 ng/mL, pD2: chemerin: 94.5±0.1 vs. veh: 23.6±0,1), which was prevented by the ChemR23 antagonist CCX 832 (pD2: veh= 16.9±0.1; chem= 174.1±0.1, CCX+chem= 37.4±0.1) and a PI3K activator (YS-49) (pD2: veh= 23.0±0.1; chem= 108.5±0.1, YS-49+chem= 28.5±0.1). Chemerin also decreased PI3K (0.8±0.1 vs. veh 1.1±0.1), Akt (0.8±0.1 vs. veh 1.2±0.1) and AMPK [0.7±0.2 vs. veh 1.0 ±0.1] phosphorylation in VSMC. IRS1 and IRS2 gene expression was decreased in VSMC stimulated with chemerin. In addition, chemerin decreased insulin-stimulated NO production in EC through activation of ChemR23 and PI3K and inhibited insulin-stimulated glucose uptake by VSMC (counts per minute: 5668±729.0 vs. veh 9923±662.7), which was mediated by ChemR23, AMPK and PI3K. Importantly, ChemR23 antagonism in diabetic (db/db) mice partially reversed decreased insulin-induced vasodilatation (mesenteric resistance arteries; pD2: db/m: 6.1±1.0; db/db: 7.3±0.2; db/db+CCX832: 6.9±0.3). In conclusion, chemerin decreases vascular insulin responses by reducing PI3K/Akt and AMPK signaling. Moreover, chemerin/ChemR23 system plays a crucial role in impaired vascular insulin signaling in diabetes, suggesting its involvement in the pathogenesis of vascular insulin resistance. Our study may contribute to a better understanding of the role of chemerin in vascular insulin dysfunction in diabetes- and obesity-associated diseases. Financial Support: FAPESP, Brazil.