Effects of Neohesperidin Dihydrochalcone (NHDC) on Oxidative Phosphorylation, Cytokine Production, and Lipid Deposition

The sweetener neohesperidin dihydrochalcone (NHDC) is a precursor for anthocyanins and has been reported to have various bioactivities, including antioxidant and hepatitis inhibitory effects. However, its inflammatory functions and mechanisms of action are poorly understood. In this study, RAW 264.7 murine macrophages were treated with NHDC and its metabolite dihydrocaffeic acid (DHCA), after which cytokine production and mitochondrial respiration were assessed. DHCA significantly down-regulated the secretion of pro-inflammatory cytokines. In contrast, NHDC had a marginal effect, suggesting that the biological metabolism of NHDC to DHCA is required for its anti-inflammatory function. However, both NHDC and DHCA rescued LPS-induced suppression of oxidative phosphorylation, which is a hallmark of anti-inflammatory M2 macrophages. 3T3-L1 adipocytes showed lower fat deposition in the presence of DHCA, while sugar-containing NHDC showed a slight increase in fat deposition. In high-fat diet-induced obese mice, treatment with NHDC successfully down-regulated body weight gain in a dose-dependent manner. Furthermore, M2 polarized bone-marrow-derived macrophages (BMDM) from NHDC-fed mice secreted an increased amount of the anti-inflammatory cytokine IL-10. Overall, these results indicate that NHDC and its physiological metabolite DHCA have the potential to suppress the inflammatory response and obese status.