The in vitro effects of resistin on the innate immune signaling pathway in isolated human subcutaneous adipocytes.
BACKGROUND
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.


OBJECTIVE
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-kappaB 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.


CONCLUSIONS
Resistin may participate in more than one mechanism to influence proinflammatory cytokine release from human adipocytes, potentially via the integration of nuclear factor-kappaB and JNK signaling pathways.
Kusminski
Christine M
CM
Unit of Diabetes and Metabolism, Clinical Sciences Research Institute, University Hospitals Coventry and Warwickshire Trust, Clifford Bridge Road, Walsgrave, Coventry CV2 2DX, United Kingdom.
da Silva
Nancy F
NF
Creely
Steven J
SJ
Fisher
Ffolliott M
FM
Harte
Alison L
AL
Baker
Adam R
AR
Kumar
Sudhesh
S
McTernan
Philip G
PG
D017667:Adipocytes / Q000187:drug effects / Q000276:immunology*; D000328:Adult; D015992:Body Mass Index; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D015850:Interleukin-6 / Q000378:metabolism; D008875:Middle Aged; D016328:NF-kappa B / Q000502:physiology; D011994:Recombinant Proteins / Q000494:pharmacology; D052243:Resistin / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects*; D012867:Skin / Q000166:cytology / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000032:analysis; D051197:Toll-Like Receptor 4 / Q000032:analysis; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D015850:Interleukin-6; D016328:NF-kappa B; C499624:RETN protein, human; D011994:Recombinant Proteins; D052243:Resistin; C495342:TLR2 protein, human; C495345:TLR4 protein, human; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D014409:Tumor Necrosis Factor-alpha