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Visfatin is regulated by rosiglitazone in type 2 diabetes mellitus and influenced by NFκB and JNK in human abdominal subcutaneous adipocytes.

McGee KC, Harte AL, da Silva NF, Al-Daghri N, Creely SJ, Kusminski CM, Tripathi G, Levick PL, Khanolkar M, Evans M, Chittari MV, Patel V, Kumar S, McTernan PG - PLoS ONE (2011)

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Unit for Diabetes & Metabolism, Clinical Sciences Research Institute, UHCW Trust, Walsgrave, Coventry, United Kingdom.

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.

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Related in: MedlinePlus

A–E. Photographs of Immunological Staining of Visfatin Protein.This figure shows the immunological staining of visfatin in (A) human kidney negative (primary antibody omitted); (B) human kidney positive control; (C) human AT PBEF negative (primary antibody omitted); (D) human Om AT; (E) human Abd Sc AT. Red arrows highlight areas of red staining to show the presence of the visfatin protein.
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pone-0020287-g001: A–E. Photographs of Immunological Staining of Visfatin Protein.This figure shows the immunological staining of visfatin in (A) human kidney negative (primary antibody omitted); (B) human kidney positive control; (C) human AT PBEF negative (primary antibody omitted); (D) human Om AT; (E) human Abd Sc AT. Red arrows highlight areas of red staining to show the presence of the visfatin protein.

Mentions: Positive immuno-staining of visfatin (Figure 1) in the cytoplasm and cell membrane was confirmed in both Om (D) and Abd Sc (E) AT. Omission of the primary visfatin antibody (C) did not reveal any positive staining. Human kidney tissue was used as a control, also undergoing primary antibody omission (A) and positive immunohistological staining for visfatin (B).


Visfatin is regulated by rosiglitazone in type 2 diabetes mellitus and influenced by NFκB and JNK in human abdominal subcutaneous adipocytes.

McGee KC, Harte AL, da Silva NF, Al-Daghri N, Creely SJ, Kusminski CM, Tripathi G, Levick PL, Khanolkar M, Evans M, Chittari MV, Patel V, Kumar S, McTernan PG - PLoS ONE (2011)

A–E. Photographs of Immunological Staining of Visfatin Protein.This figure shows the immunological staining of visfatin in (A) human kidney negative (primary antibody omitted); (B) human kidney positive control; (C) human AT PBEF negative (primary antibody omitted); (D) human Om AT; (E) human Abd Sc AT. Red arrows highlight areas of red staining to show the presence of the visfatin protein.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3111427&req=5

pone-0020287-g001: A–E. Photographs of Immunological Staining of Visfatin Protein.This figure shows the immunological staining of visfatin in (A) human kidney negative (primary antibody omitted); (B) human kidney positive control; (C) human AT PBEF negative (primary antibody omitted); (D) human Om AT; (E) human Abd Sc AT. Red arrows highlight areas of red staining to show the presence of the visfatin protein.
Mentions: Positive immuno-staining of visfatin (Figure 1) in the cytoplasm and cell membrane was confirmed in both Om (D) and Abd Sc (E) AT. Omission of the primary visfatin antibody (C) did not reveal any positive staining. Human kidney tissue was used as a control, also undergoing primary antibody omission (A) and positive immunohistological staining for visfatin (B).

Bottom Line: 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).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.

View Article: PubMed Central - PubMed

Affiliation: Unit for Diabetes & Metabolism, Clinical Sciences Research Institute, UHCW Trust, Walsgrave, Coventry, United Kingdom.

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.

Show MeSH
Related in: MedlinePlus