title: Valsartan ameliorates the constitutive adipokine expression pattern in mature adipocytes: a role for inverse agonism of the angiotensin II type 1 receptor in obesity.
abstract: Angiotensin (Ang) II receptor blockers (ARBs) alleviate obesity-related insulin resistance, which suggests an important role for the Ang II type 1 receptor (AT1R) in the regulation of adipocytokines. Therefore, we treated mature 3T3-L1 adipocytes with 50 μmol l(-1) of valsartan, a selective AT1R blocker without direct agonism to peroxisome proliferator-activated receptor (PPAR)-γ. In the absence of effective concentrations of Ang II, unstimulated mature adipocytes expressed and secreted high levels of interleukin (IL)-6. This constitutive proinflammatory activity was attenuated by the suppression of extracellular signal-regulated kinase phosphorylation by valsartan but was unaffected by the Ang II type 2 receptor blocker PD123319. COS7 cells co-transfected with AT1R and IL-6, which expressed NF-κB but lacked PPAR-γ, showed no constitutive but substantial ligand-dependent IL-6 reporter activity, which was counteracted by valsartan. Valsartan preserved cytosolic IκB-α and subsequently reduced nuclear NF-κB1 protein expression in mature adipocytes. Interestingly, valsartan did not increase PPAR-γ messenger RNA expression per se but enhanced the transcriptional activity of PPAR-γ in mature adipocytes; this enhancement was accompanied by upregulation of the PPAR coactivator (PGC)-1α. Moreover, T0090907, a PPAR-γ inhibitor, increased IL-6 expression, and this increase was attenuated by valsartan. Indeed, addition of valsartan without direct PPAR-γ agonism increased adiponectin production in mature adipocytes. Together, the findings indicate that valsartan blocks the constitutive AT1R activity involving the NF-κB pathway that limits PPAR-γ activity in mature adipocytes. Thus, inverse agonism of AT1R attenuates the spontaneous proinflammatory response and enhances the constitutive insulin-sensitizing activities of mature adipocytes, which may underlie the beneficial metabolic impacts of ARBs.
authors.affiliation: Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Arif U
authors.initials: AU
authors.lastname: Hasan
authors.affiliation: Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Ohmori
authors.affiliation: Department of Cardiovascular Physiology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Hashimoto
authors.affiliation: Department of Cell Physiology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Kazuyo
authors.initials: K
authors.lastname: Kamitori
authors.affiliation: Department of Cell Physiology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Fuminori
authors.initials: F
authors.lastname: Yamaguchi
authors.affiliation: Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Ishihara
authors.affiliation: Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Ishihara
authors.affiliation: Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Noma
authors.affiliation: Department of Cell Physiology, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Tokuda
authors.affiliation: Department of Cardiorenal and Cerebrovascular Medicine, Faculty of Medicine, Kagawa University, Kagawa, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Kohno
mesh_terms: D041721:3T3-L1 Cells; D021581:Active Transport, Cell Nucleus; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism; D054392:Adipokines / Q000235:genetics*; D000804:Angiotensin II / Q000494:pharmacology; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D054314:Drug Inverse Agonism; D015850:Interleukin-6 / Q000235:genetics; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009765:Obesity / Q000378:metabolism*; D047495:PPAR gamma / Q000502:physiology; D044140:Receptor, Angiotensin, Type 1 / Q000502:physiology*; D013777:Tetrazoles / Q000494:pharmacology*; D014633:Valine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068756:Valsartan
chemical_list: D054392:Adipokines; D047228:Angiotensin II Type 1 Receptor Blockers; D015850:Interleukin-6; D016328:NF-kappa B; D047495:PPAR gamma; D044140:Receptor, Angiotensin, Type 1; D013777:Tetrazoles; D000804:Angiotensin II; D000068756:Valsartan; D014633:Valine