胆汁酸受容体TGR5活性化による健康寿命の延伸

抄録

Bile acids exert anti-obesity and anti-hyperglycemic effects through a G protein-coupled receptor TGR5. In L cells located in the lower small intestine TGR5 activation stimulates secretion of a peptide hormone GLP-1 that enhances insulin sensitivity. In brown adipose tissues and skeletal muscles its activation results in an increase in energy expenditure, leading to anti-obesity effects. Based on these findings, we searched for food factors that mimic bile acid functions, and identified a citrus limonoid nomilin as a powerful agonist for TGR5. Simulation analyses for TGR5-nomilin association and mutation analyses of human TGR5 revealed that TGR5 is capable of biding nomilin through three amino acid residues located in a transmembrane and extracellular domain. Further analyses using transgenic mice overexpressing human TGR5 in skeletal muscles showed that TGR5 activation results in an increase in muscle mass. Taken together, we believe that TGR5 is one of ideal targets for functional food factors to extend healthy life expectancy.