Molecular Nutrition Study of the Transcriptional Regulation of Anti-obesity Hormones

(Young Investigator Award of JSNFS (2016) )

Abstract

Lifestyle-related diseases including obesity may lead to severe conditions such as cardiovascular disease. FGF19 and FGF21, expressed in the small intestine and liver, respectively, are anti-obesity hormone-like molecules. In this study, we studied novel transcriptional regulation of the FGF19 and FGF21 genes with the aim of establishing a research base for functional food factors that might prevent metabolic syndrome. Experiments using intestinal cell lines revealed that endoplasmic reticulum stress regulates expression of the FGF19 gene, and that FGF19 is a novel target gene of the transcription factor ATF4, which is activated by endoplasmic reticulum stress. We also found that ATF4 also regulates expression of the FGF21 gene as well as the FGF19 gene. ATF4 is activated by a variety of stimuli in addition to endoplasmic reticulum stress. Experiments using cell lines and mice showed that expression of the FGF19 and FGF21 genes is selectively regulated by these stimuli. These results suggest that ATF4 is a novel regulator of FGF19 and FGF21 gene expression, and a potential target molecule for prevention of metabolic syndrome.