Apolipoprotein A-IV restrains fat accumulation in skeletal and myocardial muscles by inhibiting lipogenesis and activating PI3K–AKT signalling

Abstract

Background

One of the pathological characteristics of obesity is fat accumulation of skeletal muscles (SKM) and the myocardium, involving mechanisms of insulin resistance and abnormal lipid metabolism. Apolipoprotein A-IV (ApoA-IV) is an essential gene in both glucose and lipid metabolisms.

Materials and methods

Using high-fat diet (HFD) induced obese apoA-IV-knockout mice and subsequent introduction of exogenous recombinant-ApoA-IV protein and adeno-associated virus (AAV)-transformed apoA-IV, we examined lipid metabolism indicators of SKM and the myocardium, which include triglyceride (TG) content, RT-PCR for lipogenic indicators and western blotting for AKT phosphorylation. Similarly, we used high-glucose-fed or palmitate (Pal)-induced C2C12 cells co-cultured with ApoA-IV protein to evaluate glucose uptake, the phosphoinositide 3-kinase (PI3K)–AKT pathway, and lipid metabolisms.

Results

In stable obese animal models, we find ApoA-IV-knockout mice show elevated TG content, enhanced expression of lipogenic enzymes and diminished phosphorylated AKT in SKM and the myocardium, but both stable hepatic expression of AAV-apoA-IV and brief ApoA-IV protein administration suppress lipogenesis and promote AKT phosphorylation. In a myoblast cell line C2C12, ApoA-IV protein suppresses Pal-induced lipid accumulation and lipogenesis but enhances AKT activation and glucose uptake, and the effect is abolished by a PI3K inhibitor.

Conclusion

We find that ApoA-IV reduces fat accumulation by suppressing lipogenesis and improves glucose uptake in SKM and the myocardium by regulating the PI3K–AKT pathway.

Keywords:

• Apolipoprotein A-IV
• obesity
• skeletal muscle
• myocardium
• insulin resistance
• lipid metabolism

Acknowledgements

The authors would like to thank Professor Patrick Tso (Department of Pathology and Laboratory Medicine, University of Cincinnati, Ohio, USA) for providing apoA-IV knockout mice, recombinant mouse ApoA-IV protein and antibodies of ApoA-IV.

Author contributions

Xiaoming Li conceived and designed the research; Wenqian Zhang, Xiaohuan Liu, Jinting Zhou, and Cheng Cheng conducted the experiments and analysed the data; Xiaoming Li and Wenqian Zhang drafted the paper; Jing Xu provided critical feedback and revised the manuscript. Jun Yu revised the manuscript and provided language polishing. All authors read and approved the final manuscript.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Data availability statement

The data that support the findings of this study are available from the corresponding author, Xiaoming Li, upon reasonable request.

Additional information

Funding

This work was supported by grants from the National Natural Science Foundation of China (No. 81770798) and Natural Science Foundation of Shaanxi Province (2020JM-405) to Xiaoming Li.