Adipose tissue release of interleukin-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 IL-6. 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 levels. In vitro studies also showed a direct correlation between the amount of adipose tissue and its release of ADMA. Thus, genetic, dietary and pharmacological disruption of DDAH altered adipose ADMA release. In conclusion, this work showed that two important enzymes, COX and DDAH, in adipose tissue have the capacity to modulate cardiovascular risk in obesity by their regulation of IL-6 synthesis, adipogenesis and the release of ADMA.