Vanillic acid attenuates obesity via activation of the AMPK pathway and thermogenic factors in vivo and in vitro

Energy expenditure is a target gaining recent interest for obesity treatment. The antiobesity effect of vanillic acid (VA), a well-known flavoring agent, was investigated in vivo and in vitro. High-fat diet (HFD)-induced obese mice and genetically obese db/db mice showed significantly decreased body weights after VA administration. Two major adipogenic markers, peroxisome proliferator activated receptor gamma (PPAR gamma) and CCAAT/enhancer-binding protein alpha (C/EBP alpha), were reduced while the key factor of energy metabolism, AMPK alpha, was increased in the white adipose tissue and liver tissue of VA-treated mice. Furthermore, VA inhibited lipid accumulation and reduced hepatotoxic/inflammatory markers in liver tissues of mice and HepG2 hepatocytes. VA treatment also decreased differentiation of 3T3-L1 adipocytes by regulating adipogenic factors including PPAR gamma and C/EBP alpha. AMPK alpha small interfering RNA was used to examine whether AMPK was associated with the actions of VA. In AMPK alpha-nulled 3T3-L1 cells, the inhibitory action of VA on PPAR gamma and C/EBP alpha was attenuated. Furthermore, in brown adipose tissues of mice and primary cultured brown adipocytes, VA increased mitochondria- and thermogenesis-related factors such as uncoupling protein 1 and PPAR gamma-coactivator 1-alpha. Taken together, our results suggest that VA has potential as an AMPK alpha- and thermogenesis-activating antiobesity agent.