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

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.