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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&B. The Effects of Insulin and RSG on IKKβ and JNK1/2 Protein Expression.These figures shows the effect of insulin, alone (100 nM), and insulin in combination with RSG (Ins 100 nM/RSG 10 nM) on the mean relative fold protein expression (± SEM) of IKKβ (Figure 4A) and JNK 1/2 (Figure 4B). The representative Western blots are shown above (n = 4, p-values: p<0.05*, p<0.001***).
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pone-0020287-g004: A&B. The Effects of Insulin and RSG on IKKβ and JNK1/2 Protein Expression.These figures shows the effect of insulin, alone (100 nM), and insulin in combination with RSG (Ins 100 nM/RSG 10 nM) on the mean relative fold protein expression (± SEM) of IKKβ (Figure 4A) and JNK 1/2 (Figure 4B). The representative Western blots are shown above (n = 4, p-values: p<0.05*, p<0.001***).

Mentions: In mature Abd Sc adipocytes, treatment with Ins 100 nM/RSG 10 nM was shown to significantly reduce IKKβ and JNK 1/2 protein expression (*p<0.01 and *p<0.05, respectively) compared with adipocytes treated with insulin alone (100 nM) (Figures 4A and 4B).


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&B. The Effects of Insulin and RSG on IKKβ and JNK1/2 Protein Expression.These figures shows the effect of insulin, alone (100 nM), and insulin in combination with RSG (Ins 100 nM/RSG 10 nM) on the mean relative fold protein expression (± SEM) of IKKβ (Figure 4A) and JNK 1/2 (Figure 4B). The representative Western blots are shown above (n = 4, p-values: p<0.05*, p<0.001***).
© Copyright Policy
Related In: Results  -  Collection

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

pone-0020287-g004: A&B. The Effects of Insulin and RSG on IKKβ and JNK1/2 Protein Expression.These figures shows the effect of insulin, alone (100 nM), and insulin in combination with RSG (Ins 100 nM/RSG 10 nM) on the mean relative fold protein expression (± SEM) of IKKβ (Figure 4A) and JNK 1/2 (Figure 4B). The representative Western blots are shown above (n = 4, p-values: p<0.05*, p<0.001***).
Mentions: In mature Abd Sc adipocytes, treatment with Ins 100 nM/RSG 10 nM was shown to significantly reduce IKKβ and JNK 1/2 protein expression (*p<0.01 and *p<0.05, respectively) compared with adipocytes treated with insulin alone (100 nM) (Figures 4A and 4B).

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