Vitamin K2 Alleviates Insulin Resistance in Skeletal Muscle by Improving Mitochondrial Biogenesis Through Modulating SIRT1 Signaling

Background: High-fat diet (HFD)-induced insulin resistance (IR) impairs skeletal muscle mitochondrial biogenesis and functions, adversely affecting human health and lifespan. Vitamin K2 (VK2) has a beneficial role in improving insulin sensitivity and glucose metabolism. However, the underlying molecular mechanisms of VK2 on insulin sensitivity have not been well established. We investigated VK2's modulation of mitochondrial function to protect against IR in mice and cell models. Method: C57BL/6J mice were fed HFD for sixteen weeks, and different doses of VK2 were supplemented by oral gavage for the last eight weeks. Mouse skeletal muscle C2C12 cells were exposed to palmitic acid (PA) for 16 h to mimic insulin resistance. Findings: VK2 supplementation could effectively ameliorate the development of IR by improving mitochondrial function in both HFD-fed mice and PA-exposed cells. FFA caused mitochondrial dysfunction and aggravated glucose intolerance that could be reversed by VK2 treatment. Moreover, VK2 improved the function of mitochondria and increased mitochondrial biogenesis. Interestingly, the benefits of VK2 were abrogated in C2C12 transfected with SIRT1 siRNA. VK2 and SRT1720, a specific agonist of SIRT1, had the same effect on improving IR via SIRT1 signaling. Thus, VK2 suppresses skeletal muscle IR in an SIRT1-dependent manner. Furthermore, the beneficial effect of VK2 on inhibiting IR contributes to geranylgeraniol, which also activates the SIRT1 signaling pathway. Interpretation: Naturally occurring VK2 ameliorates IR by improving mitochondrial biogenesis and decreasing FFA accumulation through modulating SIRT1 signaling. These effects of VK2 are promising therapeutic targets that can ameliorate HFD-induced IR and mitochondrial dysfunction. Funding Statement: This study was funded by National Natural Science Funds (No, 8157120149 ) and our study also was supported by Shaanxi Key Laboratory of Free Radical Biology and Medicine and Ministry of Education Key Lab of Hazard Assessment and Control in Special Operational Environment. Declaration of Interests: All authors declare no competing interest. Ethics Approval Statement: Experimental protocols were reviewed and approved by the Fourth Military Medical University Institutional Animal Care and Use Committee.