2019-P: Deletion of Hepatic SIRT1 Enhances the Effect of Ketogenic Diets on Ameliorating Obesity and Metabolic Disorders

Abstract

A ketogenic diet, one kind of carbohydrate-restricted diets, is considered to reduce body weight and improve metabolic disorders. However, the mechanism of how a ketogenic diet provides such metabolic benefits is unclear. SIRT1, a NAD-dependent deacetylase, plays an important role in lipid metabolism. We investigated the role of hepatic SIRT1 in the beneficial effect of ketogenic diets on improving obesity and metabolic disorder. In this study, eight-week-old male liver-specific SIRT1 deletion (SIRT1 LKO) mice and control mice were subjected to a high fat diet (HFD) or an intermittent ketogenic diet (iKD), ketogenic diet alternated biweekly with HFD, for 12 weeks. The results showed that the body weight of mice fed on iKD was significantly lower than mice fed on HFD, even though higher energy intake was observed when mice were fed on a ketogenic diet. Interestingly, SIRT1 LKO mice on HFD were slightly heavier than control mice on HFD, but SIRT1 LKO mice on iKD were thinner than control mice on iKD. Lower fasting blood glucose was observed after every 2-week ketogenic diets intervention, and there was no significant difference between SIRT1 LKO mice and control mice. Compared to HFD, iKD significantly improved insulin resistance. Notably, iKD improved the glucose metabolism of SIRT1 LKO mice, but such improvement was not observed in control mice. These results indicate that an intermittent ketogenic diet improves metabolic disorders induced by HFD and has further beneficial effect on obesity and metabolic disorder in the absent of hepatic SIRT1. The underlying mechanism will be further studied. Disclosure W. Guo: None. F. Xu: None. G. Li: None. H. Liang: None. M. Cai: None.