title: Angiotensin II receptor blocker ameliorates stress-induced adipose tissue inflammation and insulin resistance.
abstract: A strong causal link exists between psychological stress and insulin resistance as well with hypertension. Meanwhile, stress-related responses play critical roles in glucose metabolism in hypertensive patients. As clinical trials suggest that angiotensin-receptor blocker delays the onset of diabetes in hypertensive patients, we investigated the effects of irbesartan on stress-induced adipose tissue inflammation and insulin resistance. C57BL/6J mice were subjected to 2-week intermittent restraint stress and orally treated with vehicle, 3 and 10 mg/kg/day irbesartan. The plasma concentrations of lipid and proinflammatory cytokines [Monocyte Chemoattractant Protein-1 (MCP-1), tumor necrosis factor-α, and interleukin-6] were assessed with enzyme-linked immunosorbent assay. Monocyte/macrophage accumulation in inguinal white adipose tissue (WAT) was observed with CD11b-positive cell counts and mRNA expressions of CD68 and F4/80 using immunohistochemistry and RT-PCR methods respectively. The mRNA levels of angiotensinogen, proinflammatory cytokines shown above, and adiponectin in WAT were also assessed with RT-PCR method. Glucose metabolism was assessed by glucose tolerance tests (GTTs) and insulin tolerance tests, and mRNA expression of insulin receptor substrate-1 (IRS-1) and glucose transporter 4 (GLUT4) in WAT. Restraint stress increased monocyte accumulation, plasma free fatty acids, expression of angiotensinogen and proinflammatory cytokines including MCP-1, and reduced adiponectin. Irbesartan reduced stress-induced monocyte accumulation in WAT in a dose dependent manner. Irbesartan treatment also suppressed induction of adipose angiotensinogen and proinflammatory cytokines in WAT and blood, and reversed changes in adiponectin expression. Notably, irbesartan suppressed stress-induced reduction in adipose tissue weight and free fatty acid release, and improved insulin tolerance with restoration of IRS-1 and GLUT4 mRNA expressions in WAT. The results indicate that irbesartan improves stress-induced adipose tissue inflammation and insulin resistance. Our results suggests that irbesartan treatment exerts additive benefits for glucose metabolism in hypertensive patients with mental stress.
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Motoharu
authors.initials: M
authors.lastname: Hayashi
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Department of Clinical Laboratory, Nagoya University Hospital, Nagoya, Japan.
authors.forename: Kyosuke
authors.initials: K
authors.lastname: Takeshita
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Uchida
authors.affiliation: Department of Blood Transfusion, Nagoya University Hospital, Nagoya, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Department of Clinical Laboratory, Nagoya University Hospital, Nagoya, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Kikuchi
authors.affiliation: Department of Blood Transfusion, Aichi Medical University Hospital, Nagakute, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Nakayama
authors.affiliation: Department of Blood Transfusion, Nagoya University Hospital, Nagoya, Japan.
authors.forename: Emiko
authors.initials: E
authors.lastname: Nomura
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Xian Wu
authors.initials: XW
authors.lastname: Cheng
authors.affiliation: Department of Blood Transfusion, Nagoya University Hospital, Nagoya, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Matsushita
authors.affiliation: Department of Pathology, Nagoya University Hospital, Nagoya, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Nakamura
authors.affiliation: Department of Cardiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.
authors.forename: Toyoaki
authors.initials: T
authors.lastname: Murohara
mesh_terms: D054392:Adipokines / Q000235:genetics; D052436:Adipose Tissue, White / Q000187:drug effects / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000808:Angiotensinogen / Q000235:genetics; D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D018932:Chemokine CCL2 / Q000097:blood; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D007333:Insulin Resistance / Q000502:physiology; D000077405:Irbesartan; D008066:Lipolysis / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D015434:Panniculitis / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism; D013312:Stress, Physiological; D013777:Tetrazoles / Q000494:pharmacology*
chemical_list: D054392:Adipokines; D047228:Angiotensin II Type 1 Receptor Blockers; D001713:Biphenyl Compounds; C491768:Ccl2 protein, mouse; D018932:Chemokine CCL2; D013777:Tetrazoles; D000808:Angiotensinogen; D000077405:Irbesartan