K27Q/K29Q mutations in sphingosine kinase 1 attenuate high-fat diet induced obesity and altered glucose homeostasis in mice

Jing Xie,Haifeng Duan,Jingbo Gong,Xiuxiao Xiao,Yong Shao,Meilan Cui,Qunwei Zhang,Binghua Xue,Jin Liu,Xianwen Hu

doi:10.1038/s41598-020-77096-w

Abstract

Obesity and its associated metabolic disorders are increasingly impacting public health worldwide. Sphingosine kinase 1 (Sphk1) is a critical enzyme in sphingolipid metabolism that has been implicated in various metabolic syndromes. In this study, we developed a mouse model constitutively expressing pseudoacetylated mouse Sphk1 (QSPHK1) to study its role in regulating glucose and lipid metabolism. The results showed that QSPHK1 mice gained less body weight than wide type (WT) mice on a high-fat diet, and QSPHK1 mice had improved glucolipid metabolism and insulin. Moreover, QSPHK1 mice had alleviated hepatic triglyceride accumulation and had high-fat-diet-induced hepatic steatosis that occurred as a result of reduced lipogenesis and enhanced fatty acid oxidation, which were mediated by the AMPK/ACC axis and the FGF21/adiponectin axis. Collectively, this study provided evidence that the K27Q/K29Q mutations of Sphk1 could have a protective role in preventing obesity and the related metabolic diseases. Hence, our results contribute to further understanding of the biological functions of Sphk1, which has great pharmaceutical implications.

Highlights

Obesity and its associated metabolic disorders are increasingly impacting public health worldwide
To determine whether acetylation of sphingosine kinases (Sphks)[1] was implicated in regulating glucose and lipid metabolism, we developed, for the first time, mice carrying Q residues in the GK acetylation motif of Sphk[1] (QSPHK1 mice), and body fat accumulation and glucolipid metabolism of mice on a high-fat diet (HFD) were compared with those of wide type (WT) mice on the same diet
The results showed that QSPHK1 mice were resistant to HFD-induced obesity, hepatic steatosis, and the development of insulin resistance in addition to being able to maintain glucose homeostasis

Summary

Introduction

Obesity and its associated metabolic disorders are increasingly impacting public health worldwide. The results showed that QSPHK1 mice were resistant to HFD-induced obesity, hepatic steatosis, and the development of insulin resistance in addition to being able to maintain glucose homeostasis. After 16 weeks, QSPHK1 mice gained comparable weight with WT mice on ND, but both strains were significantly obese when fed a high-fat food compared to normal diet (Fig. 2A).

Results

Conclusion