Interplay of pro- and anti-inflammatory cytokines to determine lipid accretion in adipocytes

OBJECTIVE: Obesity is associated with an increase in various pro-inflammatory and anti-inflammatory cytokines, but the interplay of these cytokines is incompletely understood. We conducted experiments to test a broader hypothesis that a dynamic interplay of pro-inflammatory and anti-inflammatory cytokines controls lipid storage in adipocytes. DESIGN: Three experiments were designed to test the overall hypothesis that pro-inflammatory cytokine (e.g. TNF-α) inhibits anti-inflammatory cytokine (e.g. adiponectin) activity in an attempt to limit excess lipid accumulation in adipocytes. RESULTS: Experiment 1 showed that in pro-inflammatory animal models (ap2-P65, ob/ob and high fat diet-induced obese mice), the increase in TNF-α expression was associated with a decrease in adiponectin expression. Experiment 2 showed that in 3T3-L1 adipocytes, TNF-α significantly reduced lipid accumulation and glucose uptake induced by adiponectin, and increased lipolysis. Experiment 3 showed that in 3T3-L1 adipocytes, TNF-α reduced mRNA and protein expression of adiponectin. Adiponectin gene transcription and mRNA stability were both reduced by TNF-α. The expression of PPAR-γ, an activator of adiponectin gene promoter, was reduced by TNF-α. The inhibitory activity of TNF-α was blocked by chemical inhibitors of NF-κB and super suppressor IκBα (ssIκBα). CONCLUSION: TNF-α opposes the action of adiponectin in the regulation of lipid metabolism, and inhibits adiponectin expression at transcriptional and post-transcriptional levels. The results suggest that pro-inflammatory cytokine inhibit anti-inflammatory cytokine in adipocytes to reduce lipid storage. This suggests a potential role of anti-inflammatory cytokines in the control of adipose tissue expansion.