Nobiletin and 3'-Demethyl Nobiletin Activate Brown Adipocytes upon ß-Adrenergic Stimulation.

Brown adipose tissue (BAT) specifically regulates energy expenditure via heat production. Nobiletin (NOB), a natural polymethoxylated flavone present in citrus fruits, can activate thermogenesis in the BAT of high-fat diet-induced obese mice. The activity of BAT is directly regulated by ß-adrenergic stimulation. In this study, we report the effects of NOB on BAT activation using ß-adrenergic agonists. We observed that when HB2 brown adipocyte cell lines are stimulated with ß-adrenergic agonists, NOB enhances the expression of uncoupling protein 1 (UCP1), which is associated with the mitochondrial energy metabolism in these cells. Moreover, NOB increases the mRNA expression of the brown adipokines neuregulin-4 (Nrg4) and fibroblast growth factor-21 (FGF-21) and the secretion of FGF-21. These results suggest that NOB can enhance the thermogenic functions of brown adipocytes and promote brown adipokine secretion due to enhanced ß-adrenergic stimulation. In addition, 3'-demethyl nobiletin (3'-DMN), an NOB CYP-enzyme metabolite, can increase UCP1 mRNA expression. Both NOB and 3'-DMN significantly promoted mitochondrial membrane potential in HB2 adipocytes following ß-adrenergic stimulation. Therefore, we believe that NOB could be a promising candidate for activating BAT under ß-adrenergic stimulation and preventing the onset of obesity.