4-hydroxy-3-methoxycinnamic acid (ferulic acid, FA) is known to have numerous beneficial health effects, including anti-obesity and anti-hyperglycemic properties. However, the molecular networks that modulate the beneficial FA-induced metabolic effects have not been well elucidated. In this study, we explored the molecular mechanisms mediating the beneficial metabolic effects of FA. In mice, FA protected against high-fat diet-induced weight gain, reduced food intake and exhibited an overall improved metabolic phenotype. The food intake suppression by FA was accompanied by a specific reduction in hypothalamic orexigenic neuropeptides, including agouti-related protein and neuropeptide Y, with no significant changes in the anorexigenic peptides pro-opiomelanocortin and cocaine and amphetamine-regulated transcript. FA treatment also inhibited fat accumulation in the liver and white adipose tissue and suppressed the expression of gluconeogenic genes, including phosphoenolpyruvate carboxylase and glucose-6-phosphatase. Furthermore, we show that FA phosphorylated and inactivated the transcription factor FoxO1, which positively regulates the expression of gluconeogenic and orexigenic genes, providing evidence that FA might exert its beneficial metabolic effects through inhibition of FoxO1 function in the periphery and the hypothalamus.
Bibliographical noteFunding Information:
We thank Dr Min-Seon Kim (Asan Medical Center) for the POMC, AgRP and NPY luciferase constructs and Dr Heung-Sik Choi (Chonnam National University) for the PEPCK and G6P luciferase constructs. This work was supported by the Ministry of Oceans and Fisheries (20150071) and the Korean Government and Korea Industrial Technology Association (20170109) for SHM and National Research Foundation (2016R1C1B3012748, 2014K1A3A1A19066980 and 2017R1A5A2015369) and Korea Health Industry Development Institute (HI17C0745) for KWK. Author contributions: AWK conceptualized the research, performed experiments, analyzed data and wrote the manuscript. CMK, KVD, DJY, MKQH, SHM and YHC performed experiments and analyzed data. KWK conceptualized the research, analyzed data, and edited and finalized the manuscript.
© 2018 The Author(s).
All Science Journal Classification (ASJC) codes
- Molecular Medicine
- Molecular Biology
- Clinical Biochemistry