Identification of α-ionone, nootkatone, and their derivatives as TGR5 agonists

• Published in: Biochemical and biophysical research communications 2023-04, Vol.653, p.147-152
• Main Authors: Sasaki, Takashi, Ikari, Naho, Hashimoto, Shuzo, Sato, Ryuichiro
• Format: Article
• Language: English
• Subjects: Adipose Tissue, Brown - metabolism; Animals; Bile Acids and Salts - metabolism; Brown adipose tissue; Diet, High-Fat - adverse effects; Energy Metabolism; High-fat diet; Mice; Mice, Inbred C57BL; Nootkatone; Obesity - metabolism; Polycyclic Sesquiterpenes - metabolism; Polycyclic Sesquiterpenes - pharmacology; Polycyclic Sesquiterpenes - therapeutic use; TGR5; Thermogenesis; α-ionone
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2023.02.070

TGR5 is a G-protein-coupled receptor that is activated by bile acids. The activation of TGR5 in brown adipose tissue (BAT) increases energy expenditure by increasing the expression level of thermogenesis-related genes, such as peroxisome proliferator-activated receptor-gamma coactivator 1-alpha, uncoupling protein 1, and type II iodothyronine deiodinase. Therefore, TGR5 is a potential drug target in treating obesity and associated metabolic disorders. In this study, we identified the aroma compounds α-ionone and nootkatone as well as their derivatives as TGR5 agonists by using the luciferase reporter assay system. These compounds had little effect on the activity of the farnesoid X receptor, a nuclear receptor activated by bile acids. Mice fed 0.2% α-ionone containing high-fat diet (HFD) increased the thermogenesis-related gene expression level in BAT and suppressed weight gain compared with mice fed a normal HFD. These findings indicate that aromatic compounds with TGR5 agonist activity are promising chemicals to prevent obesity. •α-Ionone and nootkatone were identified as TGR5 agonists.•The major derivatives of α-ionone and nootkatone also activated TGR5.•Dietary α-ionone suppressed diet-induced obesity in mice.