The Cholesterol Metabolite Cholest-5-en-3-One Alleviates Hyperglycemia and Hyperinsulinemia in Obese (db/db) Mice

Dietary sterols are catabolized into various substances in the intestinal tract. Dietary 3-oxo derivatives of cholesterol and plant sterols (e.g., cholest-4-en-3-one and campest-5-en-3-one) have been shown to have anti-obesity effects. In this study, we tested whether feeding cholest-5-en-3-one (5-cholestenone), a cholesterol metabolite, to db/db mice protects them from obesity-associated metabolic disorders. In db/db mice, dietary 5-cholestenone significantly alleviated hepatomegaly and elevated serum triglyceride levels; however, the effect was not sufficient to improve hepatic steatosis and obesity. On the other hand, hyperglycemia and severe hyperinsulinemia in control db/db mice were markedly attenuated in 5-cholestenone-fed db/db mice. The production of inflammatory cytokines, such as monocyte chemoattractant protein-1, interleukin-6, and tumor necrosis factor-alpha (TNFα), was decreased, suggesting that the suppressive actions of 5-cholestenone were attributable to the alleviation of chronic inflammation in db/db mice. Additionally, 5-cholestenone showed an inhibitory effect on TNFα-induced nuclear factor kappa B (NFκB) activation in the NFκB luciferase gene reporter assay. These results suggest that obesity-induced abnormal glucose metabolism could be alleviated in 5-cholestenone-fed db/db mice by reducing the production of inflammatory cytokines through suppression of the NFκB signaling pathway.