Aims: 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. Results: VK2 supplementation could effectively ameliorate the development of IR by improving mitochondrial function in both HFD-fed mice and palmitate acid-exposed cells. We revealed for the first time that HFD-caused mitochondrial dysfunction could be reversed by VK2 treatment. VK2 enhanced the mitochondrial function by improving mitochondrial respiratory capacity, increasing mitochondrial biogenesis and the enzymatic activities of mitochondrial complexes through SIRT1 signaling. The benefits of VK2 were abrogated in C₂C₁₂ transfected with SIRT1 siRNA but not in C₂C₁₂ transfected with AMPK siRNA. VK2 and SRT1720, a specific agonist of SIRT1, had the same effect on improving mitochondrial function via SIRT1 signaling. Thus, SIRT1 is required for VK2 improvement in skeletal muscle. Further, the beneficial effects of both VK2 and geranylgeraniol contribute to inhibited IR in skeletal muscle via SIRT1. Innovation and Conclusion: These studies demonstrated a previously undiscovered mechanism by which VK2 alleviates IR in skeletal muscle by improving mitochondrial function via SIRT1. Naturally occurring VK2 prevents IR by improving mitochondrial function through SIRT1 signaling. These results could provide a foundation to identify new VK2-based preventive and therapeutic strategies for IR.

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