title: Visfatin is regulated by rosiglitazone in type 2 diabetes mellitus and influenced by NFκB and JNK in human abdominal subcutaneous adipocytes.
abstract: Visfatin has been proposed as an insulin-mimicking adipocytokine, predominantly secreted from adipose tissue and correlated with obesity. However, recent studies suggest visfatin may act as a proinflammatory cytokine. Our studies sought to determine the significance of this adipocytokine and its potential role in the pathogenesis of T2DM. Firstly, we examined the effects of diabetic status on circulating visfatin levels, and several other adipocytokines, demonstrating that diabetic status increased visfatin*, TNF-α*** and IL-6*** compared with non-diabetic subjects (*p<0.05, **p<0.01, ***p<0.001, respectively). We then assessed the effects of an insulin sensitizer, rosiglitazone (RSG), in treatment naïve T2DM subjects, on circulating visfatin levels. Our findings showed that visfatin was reduced post-RSG treatment [vs. pre-treatment (*p<0.05)] accompanied by a reduction in HOMA-IR**, thus implicating a role for insulin in visfatin regulation. Further studies addressed the intracellular mechanisms by which visfatin may be regulated, and may exert pro-inflammatory effects, in human abdominal subcutaneous (Abd Sc) adipocytes. Following insulin (Ins) and RSG treatment, our in vitro findings highlighted that insulin (100 nM), alone, upregulated visfatin protein expression whereas, in combination with RSG (10 nM), it reduced visfatin*, IKKβ** and p-JNK1/2*. Furthermore, inhibition of JNK protein exacted a significant reduction in visfatin expression (**p<0.01), whilst NF-κB blockade increased visfatin (*p<0.05), thus identifying JNK as the more influential factor in visfatin regulation. Additional in vitro analysis on adipokines regulating visfatin showed that only Abd Sc adipocytes treated with recombinant human (rh)IL-6 increased visfatin protein (*p<0.05), whilst rh visfatin treatment, itself, had no influence on TNF-α, IL-6 or resistin secretion from Sc adipocytes. These data highlight visfatin's regulation by insulin and RSG, potentially acting through NF-κB and JNK mechanisms, with only rh IL-6 modestly affecting visfatin regulation. Taken together, these findings suggest that visfatin may represent a pro-inflammatory cytokine that is influenced by insulin/insulin sensitivity via the NF-κB and JNK pathways.
authors.affiliation: Unit for Diabetes & Metabolism, Clinical Sciences Research Institute, UHCW Trust, Walsgrave, Coventry, United Kingdom.
authors.forename: Kirsty C
authors.initials: KC
authors.lastname: McGee
authors.forename: Alison L
authors.initials: AL
authors.lastname: Harte
authors.forename: Nancy F
authors.initials: NF
authors.lastname: da Silva
authors.forename: Nasser
authors.initials: N
authors.lastname: Al-Daghri
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Creely
authors.forename: Christine M
authors.initials: CM
authors.lastname: Kusminski
authors.forename: Gyanendra
authors.initials: G
authors.lastname: Tripathi
authors.forename: Paul L
authors.initials: PL
authors.lastname: Levick
authors.forename: Manish
authors.initials: M
authors.lastname: Khanolkar
authors.forename: Marc
authors.initials: M
authors.lastname: Evans
authors.forename: Madhu V
authors.initials: MV
authors.lastname: Chittari
authors.forename: Vinod
authors.initials: V
authors.lastname: Patel
authors.forename: Sudhesh
authors.initials: S
authors.lastname: Kumar
authors.forename: Philip G
authors.initials: PG
authors.lastname: McTernan
mesh_terms: D017667:Adipocytes / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D054392:Adipokines / Q000378:metabolism; D050154:Adiposity / Q000187:drug effects; D000328:Adult; D016022:Case-Control Studies; D002469:Cell Separation; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016207:Cytokines / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy / Q000201:enzymology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism; D007150:Immunohistochemistry; D007328:Insulin / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008297:Male; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D054409:Nicotinamide Phosphoribosyltransferase / Q000097:blood / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D011994:Recombinant Proteins / Q000494:pharmacology; D000077154:Rosiglitazone; D050507:Subcutaneous Fat, Abdominal / Q000166:cytology*; D045162:Thiazolidinediones / Q000494:pharmacology* / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D054392:Adipokines; D017077:Culture Media, Conditioned; D016207:Cytokines; D007328:Insulin; D016328:NF-kappa B; D011994:Recombinant Proteins; D045162:Thiazolidinediones; D014409:Tumor Necrosis Factor-alpha; D000077154:Rosiglitazone; D054409:Nicotinamide Phosphoribosyltransferase; C085455:nicotinamide phosphoribosyltransferase, human; D051550:I-kappa B Kinase; D048031:JNK Mitogen-Activated Protein Kinases