Theobromine, a Methylxanthine in Cocoa Bean, Stimulates Thermogenesis by Inducing White Fat Browning and Activating Brown Adipocytes

Natural medicinal compounds to treat obesity have recently attracted a great deal of attention because of the serious side effects of synthetic anti-obesity drugs. Recent advances have been made to identify natural products showing thermogenic activity, which is responsible for energy expenditure in brown or brown-like (beige) adipocytes. Here, we explored the thermogenic effects of theobromine, one of the most abundant methylxanthines in cocoa, on 3T3-L1 white adipocytes and HIB1B brown adipocytes. Theobromine markedly increased the expression levels of brown-fat signature proteins (PGC-1α, PRDM16, and UCP1) and beige-specific genes (Cd137, Cidea, Cited1, Tbx1, and Tmen26) in 3T3-L1 white adipocytes and remarkably elevated the expression levels of brown fatspecific genes (Cidea, Lhx8, Ppargc1, Prdm16, Ucp1, and Zic1) in HIB1B brown adipocytes. Theobromine also reduced the expression of the key adipogenic transcription factors, C/EBPα and PPARγ, in white adipocytes, while enhancing their expression in HIB1B cells. In addition, theobromine regulated lipolytic events and fat oxidation by upregulating the expression of pACC, ATGL, pHSL, ACOX, and CPT1. Additional mechanistic study revealed that theobromine activates β3-AR and AMPK. In summary, our results provide evidence for the first time indicating that theobromine has a potential beneficial effect on browning of white adipocytes and improves lipid catabolic metabolism in both cultured white and brown adipocytes via β-adrenergic signaling and AMPK activation. Consumption of theobromine may be a feasible way to activate thermogenesis and improve systematic lipid metabolism to protect against obesity and other metabolic disorders.