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The in Vitro Effects of Resistin on the Innate Immune Signaling Pathway in Isolated Human Subcutaneous Adipocytes

Unit of Diabetes and Metabolism, Clinical Sciences Research Institute, University Hospitals Coventry and Warwickshire Trust, Walsgrave, Coventry CV2 2DX, United Kingdom

Address all correspondence and requests for reprints to: Dr. P. G. McTernan, Unit of Diabetes and Metabolism, Clinical Sciences Research Institute, University Hospitals Coventry and Warwickshire Trust, Clifford Bridge Road, Walsgrave, Coventry CV2 2DX, United Kingdom. E-mail: p.g.mcternan{at}warwick.ac.uk.

Context: Obesity-associated inflammation is a contributory factor in the pathogenesis of type 2 diabetes mellitus (T2DM); the mechanisms underlying the progression to T2DM are unclear. The adipokine resistin has demonstrated proinflammatory properties in relation to obesity and T2DM.

Objectives: The objectives of this study were to characterize resistin expression in human obesity and address the role of resistin in the innate immune pathway; to examine the influence of lipopolysaccharide, recombinant human resistin (rhResistin), insulin, and rosiglitazone in human adipocytes; and, finally, to analyze the effect of rhResistin on the expression of components of the nuclear factor-B pathway and insulin signaling cascade.

Methods: Abdominal sc adipose tissue was obtained from patients undergoing elective liposuction surgery (n = 35; age, 36–49 yr; body mass index, 26.5 ± 5.9 kg/m²). Isolated adipocytes were cultured with rhResistin (10–50 ng/ml). The level of cytokine secretion from isolated adipocytes was examined by ELISA. The effect of rhResistin on protein expression of components of the innate immune pathway was examined by Western blot.

Results: In vitro studies demonstrated that antigenic stimuli increase resistin secretion (P < 0.001) from isolated adipocytes. Proinflammatory cytokine levels were increased in response to rhResistin (P < 0.001); this was attenuated by rosiglitazone (P < 0.01). When examining components of the innate immune pathway, rhResistin stimulated Toll-like receptor-2 protein expression. Similarly, mediators of the insulin signaling pathway, phosphospecific c-Jun NH₂-terminal kinase (JNK) 1 and JNK2, were up-regulated in response to rhResistin.

Conclusion: Resistin may participate in more than one mechanism to influence proinflammatory cytokine release from human adipocytes, potentially via the integration of nuclear factor-B and JNK signaling pathways.

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