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.
Highlights
Following the recent isolation and characterization of visfatin, or pre-B-cell colony-enhancing factor (PBEF)/nicotinamide phosphoribosyltransferase (Nampt), as a novel adipocytokine, there has been a rapidly growing interest in this protein, its potential properties and subsequent role in the development of T2DM and obesity
Pearson coefficient correlations were carried out to assess the relationship between circulating visfatin levels and increasing age or BMI, and a moderate, positive correlation was observed between visfatin and BMI in ND control subjects (*p,0.05)
Serum analysis revealed a significant elevation in TNF-a (***p,0.001), IL-6 (***p,0.001), glucose (***p,0.001), HOMA-IR (*p,0.05) and sCD14 (***p,0.001) levels in T2DM subjects when compared against ND subjects (Table 1)
Summary
Following the recent isolation and characterization of visfatin, or pre-B-cell colony-enhancing factor (PBEF)/nicotinamide phosphoribosyltransferase (Nampt), as a novel adipocytokine, there has been a rapidly growing interest in this protein, its potential properties and subsequent role in the development of T2DM and obesity. Whilst the role of visfatin remains unclear, ablation of the gene proves fatal in visfatin knockout (KO) mice (2/2), during early embryogenesis [1]. These findings, in addition to the high level of evolutionary conservation of the visfatin gene [2], highlight its fundamental importance and emphasize how visfatin may play a key functional role in a variety of essential biological processes. Following identification of the suggested insulin-mimetic properties of visfatin, studies have concurrently examined the role of insulin sensitizers, such as the thiazolidinediones (TZDs), on visfatin levels, which has resulted in the further generation of conflicting data. Studies investigating the relationship between visfatin expression, adiposity and depotspecificity in human and rodent AT has produced conflicting data [1,7,18,19,20,21]
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