Effects of pro-inflammatory cytokines and chemokines on leptin production in human adipose tissue in vitro.

Leptin is synthesized in adipocytes and acts primarily through central pathways suppressing appetite and increasing the metabolic rate in rodents as well as in humans. Recently leptin has also been suggested to have peripheral effects and be involved in insulin action. Since cytokines and chemokines may have effects on appetite regulation as well as on some of the obesity-related complications e.g. insulin resistance and cardiovascular disease, we investigated the effects of various cytokines and chemokines on leptin production in human adipose tissue fragments in vitro. Abdominal subcutaneous adipose tissue from healthy normal to overweight females was incubated for up to 48 h with the cytokines: tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) and interleukin-1beta (IL-1beta) and the chemokine: interleukin-8 (IL-8). IL-1beta (50 ng/ml) and TNF-alpha (10 ng/ml) decreased leptin production by 30-50% (P<0.05) and gene expression by 80-90% (P<0.05). In contrast, IL-6 and IL-8 had no effect on either leptin production or leptin gene expression. Interestingly, IL-1beta elicited a biphasic effect on leptin release with an incremental phase observed within 4 h with no concomitant change in leptin gene expression, followed by a long-lasting inhibition of leptin release and leptin gene expression. This could suggest that IL-1beta through a post-translational pathway induced an acute increase in leptin-secretion, perhaps through the release of leptin from a pre-formed pool within the adipose tissue. The long-term decrease in both leptin secretion and transcription could indicate that pro-inflammatory cytokines such as IL-1beta and TNF-alpha might influence the circulating leptin levels and thereby influence the adipose tissue to brain signalling, which could be of importance in relation to the obesity-associated diseases such as insulin resistance and cardiovascular disease.