Endocrine Abstracts (2004) 7 OC37

Resistin as an acute phase reactant and a positive mediator of IL-6 and TNF-alpha secretion in isolated human subcutaneous adipocytes

C Kusminski1, PG McTernan1, FFM Fisher1, G Valsamakis2, R Chetty1, AL Harte1 & S Kumar1

1Unit for Diabetes and Metabolism, Warwick Medical School, University of Warwick, Coventry, UK; 2Heartlands Hospital, Birmingham, UK.

Chronic sub-clinical inflammation is associated with both type 2 diabetes and related vascular complications which is coupled with pro-inflammatory markers, such as IL-6, TNF-alpha and C-reactive protein (CRP). Resistin is the latest protein to be linked with inflammation and insulin resistance in obesity. Adipose tissue has been previously established as a source of circulating resistin, TNF-alpha and IL-6. As our previous studies demonstrated a correlation between serum resistin and CRP (p<0.04; n=79) we investigated a) the effect of agents that activate the innate immune system on the secretion of resistin and other pro-inflammatory cytokines; b) the effect of resistin in stimulating secretion of other inflammatory cytokines from adipose tissue. Initial studies examined the effect of obesity on resistin protein expression using western blotting. Ex vivo abdominal subcutaneous (Sc) adipose tissue protein extracted from lean (BMI: 22.1plus/minus(SD)2.2; n=4) and obese (BMI: 33.9plus/minus6.9; n=4) subjects showed a 3 fold increase in resistin protein expression in obese subjects compared with lean subjects (non-obese: 1.0plus/minus0.23; obese: 4.3plus/minus0.33; p<0.01). Next we examined the effect of antigenic stimuli on resistin secretion in isolated Sc adipocytes. Sc adipocytes were treated (14hr) with either fungal (zymosan; 30nanograms) or a bacterial (lipoplysacharide (LPS); 10nanograms) antigen. Analysis of resistin secretion in response to these antigens indicated that both zymosan and LPS increased resistin secretion (control: 1.24plus/minus(SE)2.1nanograms per millilitre; zymosan: 3.1plus/minus0.3nanograms per millilitre***; LPS: 2.75plus/minus0.4nanograms per millilitre***; ***p<0.001; (n=7)). Additionally, Sc adipocytes were treated with human recombinant resistin (30nanograms per millilitre) which elevated the secretion of IL-6 (control: 1962plus/minus(SEM)130picograms per millilitre; resistin 30nanograms per millilitre: 2906.4plus/minus297.0picograms per millilitre; p=0.0026) and TNF-alpha compared to control (control: 74plus/minus(SEM)10picograms per millilitre; resistin 30nanograms per millilitre: 249.4plus/minus36.5; p=0.001). In conclusion, resistin represents an acute phase reactant to antigenic stimuli and further recruits inflammatory cytokines including IL-6 and TNF-alpha. These findings explain the close association of resistin to CRP and other pro-inflammatory cytokines and obesity mediated insulin resistance.

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