Adipose Tissue Release of lnterleukin-6 (IL-6) and Asymmetric Dimethyl Arginine (ADMA): Implications for Obesity Associated Metabolic Disease

Obesity is associated with the development of various metabolic diseases. Adipose tissue-derived factors may underlie this relationship. Two novel adipose signals associated with increased risk of coronary heart disease were investigated; interleukin-6 (IL-6) and the endogenous nitric oxide inhibitor, asymmetric dimethyl arginine (ADMA). The effect of the cyclo-oxygenase (COX) pathway on basal adipose IL-6 production was examined. Basal COX-2 expression was detected in adipose tissue explants. There was a dose-dependent decrease in adipose IL-6 release by a non-selective COX inhibitor, aspirin. Cyclic AMP, and not Ca2+, was the intracellular mediator of IL-6 release. PGE2 EP2 and 4 signalling is mediated by elevation in intracellular cAMP and agonists for these receptors elevated IL6. Thus, basal IL-6 secretion occurs through increased COX-2 mediated PGE2 release signalling via EP4 receptors and elevated intracellular cAMP. The role of the COX pathway was also investigated in adipogenesis. Aspirin and SC-560, a selective COX-1 inhibitor, inhibited adipocyte differentiation mainly by down-regulating adipogenic transcription factors. However, NS-398, a COX-2 selective inhibitor, was found to have no such effect. Thus, adipogenesis was found to be regulated by a COX-1 mediated mechanism. ADMA, an endogenous NO inhibitor, is cleared mainly by catabolism by DDAH. Significant amounts of DDAH 1 and 2 mRNA and protein were expressed in mouse and human adipose tissue and adipocytes. In human subjects, the abdominal sub-cutaneous adipose tissue released ADMA in vivo and circulating levels in morbid obesity were elevated. Furthermore, weight loss increased adipose DDAH expression and decreased systemic ADMA