Nobiletin Attenuates the Inflammatory Response Through Heme Oxygenase-1 Induction in the Crosstalk Between Adipocytes and Macrophages.

Crosstalk between adipocytes and macrophages has been suggested to play a crucial role in metabolic disorders such as obesity, insulin resistance, and type 2 diabetes. The objective of this study was to evaluate the effect of nobiletin on the interaction between adipocytes and macrophages. The results showed that nobiletin significantly and dose-dependently inhibited the secretion of inflammatory mediators, such as nitric oxide (NO), tumor necrosis factor (TNF-α), and monocyte chemoattractant protein (MCP)-1, in a coculture of adipocytes and macrophages. The expression of adipogenic transcription factors, including peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), in differentiated 3T3-L1 cells cocultured in transwell system was blocked by nobiletin. Nobiletin also downregulated the expression of inducible NO synthase in cocultured differentiated RAW264.7 cells. Furthermore, heme oxygenase-1 (HO-1) was significantly induced by nobiletin treatment in both cell types, and small interfering (si) RNA-mediated knockdown of HO-1 significantly recovered the inhibitory effects of nobiletin on the NO production in cocultured cells. These results suggest that nobiletin exerts anti-inflammatory effects on the crosstalk between adipocytes and macrophages by inducing HO-1. Nobiletin may have potential for the prevention of obesity-related metabolic diseases.