Chemerin/ChemR23 system plays crucial role upon vascular insulin signaling in db/db mice

The adipokine chemerin and its receptor, chemokine‐like receptor 1 (ChemR23), influence 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 impairs vascular insulin signaling via PI3K/Akt and that ChemR23 antagonism improves insulin signaling in diabetic mice. Lean (db/m) and obese and diabetic (db/db) mice were treated for 03 weeks by oral gavage with CCX 832 (ChemR23 antagonist). Mesenteric arteries, aorta and perivascular adipose tissue (PVAT) were isolated to perform functional and molecular experiments. Plasma levels of chemerin and body weight were increased in db/db mice compared to their counterpart controls db/m. However, db/db mice treated with ChemR23 antagonist (CCX 832) exhibited a slightly decrease in body weight. ChemR23 antagonism in db/db mice partially reversed decreased insulin‐induced vasodilatation (mesenteric resistance arteries; Emax: db/m: 60.75±4.09; db/db: 40.84±2.38; db/m + CCX832: 67.87±8.93; db/db + CCX832: 50.17±3.84). CCX 832 prevented the rise in glucose and insulin levels observed in db/db mice. In aorta, there was a decrease in PI3K, Akt and IRS1 phosphorylation as well as in GLUT4 protein expression in db/db mice. Treatment of animals with ChemR23 antagonist increased GLUT4 protein expression and IRS1 phosphorylation, with a trend to augmented PI3K and Akt phosphorylation. db/db mice exhibited increased vascular ROS generation, which was decrease by CCX 832. M2 macrophages markers mRNA expression (IL‐10 and CD206) in PVAT was decreased in db/db mice and treatment with ChemR23 antagonist prevented this effect. However, no changes were observed in M1 macrophages markers mRNA levels. CCX 832 also blunted the rise in MCP‐1 and TNF‐α gene expression in PVAT from db/db mice. CCX 832 increased plasma and PVAT adiponectin levels, which were reduced in db/db mice. In conclusion, ChemR23 antagonism by CCX 832 (1) decreases body weight of db/db mice; (2) partially restores vascular function in db/db mice; (3) improves insulin signaling in aorta from diabetic mice; (4) decreases the inflammatory profile of adipocytes from db/db mice; (5) decreases vascular oxidative stress in db/db mice. These findings indicate that chemerin/ChemR23 axis may contribute to inflammation, oxidative stress and decreased vascular insulin signaling in diabetes. Our study may contribute to a better understanding of the role of chemerin in vascular dysfunction in diabetes‐ and obesity‐associated diseases. Support or Funding Information FAPESP 2012/13144‐8; 2015/01630‐3.