title: Obesity-associated Gingival Vascular Inflammation and Insulin Resistance.
abstract: Obesity is a risk factor for periodontitis, but the pathogenic mechanism involved is unclear. We studied the effects of insulin in periodontal tissues during the state of obesity-induced insulin resistance. Gingival samples were collected from fatty (ZF) and lean (ZL, control) Zucker rats. Endothelial nitric oxide synthase (eNOS) expression was decreased, and activities of protein kinase C (PKC) α, ß2, δ, and ϵ isoforms were significantly increased in the gingiva from ZF rats compared with those from ZL rats. Expression of oxidative stress markers (mRNA) and the p65 subunit of NF-κB was significantly increased in ZF rats. Immunohistochemistry revealed that NF-κB activation was also increased in the gingival endothelial cells from transgenic mice overexpressing NF-κB-dependent enhanced green fluorescent protein (GFP) and on a high-fat vs. normal chow diet. Analysis of the gingiva showed that insulin-induced phosphorylation of IRS-1, Akt, and eNOS was significantly decreased in ZF rats, but Erk1/2 activation was not affected. General PKC inhibitor and an anti-oxidant normalized the action of insulin on Akt and eNOS activation in the gingiva from ZF rats. This provided the first documentation of obesity-induced insulin resistance in the gingiva. Analysis of our data suggested that PKC activation and oxidative stress may selectively inhibit insulin-induced Akt and eNOS activation, causing endothelial dysfunction and inflammation.
authors.affiliation: Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA Department of Periodontology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Mizutani
authors.affiliation: Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
authors.forename: K
authors.initials: K
authors.lastname: Park
authors.affiliation: Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA Department of Nephrology and Hematology, Nara Hospital, Kinki University Faculty of Medicine, Osaka, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Mima
authors.affiliation: Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
authors.forename: S
authors.initials: S
authors.lastname: Katagiri
authors.affiliation: Vascular Cell Biology, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA George.King@joslin.harvard.edu.
authors.forename: G L
authors.initials: GL
authors.lastname: King
mesh_terms: D016301:Alveolar Bone Loss / Q000209:etiology / Q000378:metabolism; D000818:Animals; D042783:Endothelial Cells / Q000737:chemistry; D004730:Endothelium, Vascular / Q000737:chemistry; D005891:Gingivitis / Q000209:etiology* / Q000378:metabolism; D055504:Insulin Receptor Substrate Proteins / Q000032:analysis; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D052250:Nitric Oxide Synthase Type III / Q000032:analysis; D009765:Obesity / Q000150:complications*; D051058:Oncogene Protein v-akt / Q000032:analysis; D018384:Oxidative Stress / Q000502:physiology; D064546:Protein Kinase C beta / Q000032:analysis; D051571:Protein Kinase C-alpha / Q000032:analysis; D051745:Protein Kinase C-delta / Q000032:analysis; D051744:Protein Kinase C-epsilon / Q000032:analysis; D051381:Rats; D011924:Rats, Zucker; D051996:Transcription Factor RelA / Q000032:analysis; D014657:Vasculitis / Q000209:etiology* / Q000378:metabolism
chemical_list: D055504:Insulin Receptor Substrate Proteins; C526296:Irs1 protein, rat; C498145:Rela protein, rat; D051996:Transcription Factor RelA; D052250:Nitric Oxide Synthase Type III; D051058:Oncogene Protein v-akt; D064546:Protein Kinase C beta; D051571:Protein Kinase C-alpha; D051745:Protein Kinase C-delta; D051744:Protein Kinase C-epsilon
keywords: NF-kappa B; endothelial nitric oxide synthase; oxidative stress; periodontal bone loss; periodontitis; protein kinase C
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