Medical School, University of Chinese Academy of Sciences, Beijing, 101400, China.
Beijing Key Laboratory of New Drug Mechanisms and Pharmacological Evaluation Study, Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100050, China.
Acta Pharmacol Sin. 2020 Mar;41(3):383-393. doi: 10.1038/s41401-019-0311-z. Epub 2019 Oct 28.
Osteocalcin, expressed in osteoblasts of the bone marrow, undergoes post-translational carboxylation and deposits in mineralized bone matrix. A portion of osteocalcin remains uncarboxylated (uncarboxylated osteocalcin, GluOC) that is released into blood where it functions as a hormone to regulate insulin secretion and insulin sensitivity. As insulin resistance is closely associated with metabolic syndrome, this study is aimed to elucidate how GluOC regulates glucose and lipid metabolism in KKAy mice, an animal model displaying obese, hyperglycemia, hyperinsulinemia, insulin resistance, and hepatic steatosis. GluOC (3, 30 ng/g per day, ig) was orally administered to female KKAy mice for 4 weeks. Whole-body insulin sensitivity, glucose metabolism, hepatic steatosis, dyslipidemia were examined using routine laboratory assays. We found that GluOC administration significantly enhanced insulin sensitivity in KKAy mice by activating hepatic IRβ/PI3K/Akt pathway and elevated the whole-body insulin sensitivity with decreased FPI and HOMA-IR index. Furthermore, GluOC administration alleviated hyperglycemia through suppressing gluconeogenesis and promoting glycogen synthesis in KKAy mice and in cultured hepatocytes in vitro. Moreover, GluOC administration dose-dependently ameliorated dyslipidemia and attenuated hepatic steatosis in KKAy mice by inhibiting hepatic de novo lipogenesis and promoting fatty-acid β-oxidation. These results demonstrate that GluOC effectively enhances hepatic insulin sensitivity, improves hyperglycemia and ameliorates hepatic steatosis in KKAy mice, suggesting that GluOC could be a promising drug candidate for treating metabolic syndrome.
骨钙素在骨髓中的成骨细胞中表达，经历翻译后羧化，并沉积在矿化的骨基质中。一部分骨钙素未发生羧化（未羧化骨钙素，GluOC），释放到血液中作为激素发挥作用，调节胰岛素分泌和胰岛素敏感性。由于胰岛素抵抗与代谢综合征密切相关，本研究旨在阐明 GluOC 如何调节 KKAy 小鼠（一种表现出肥胖、高血糖、高胰岛素血症、胰岛素抵抗和肝脂肪变性的动物模型）中的葡萄糖和脂质代谢。将 GluOC（每天 3、30ng/g，ig）口服给予雌性 KKAy 小鼠 4 周。使用常规实验室检测方法检查全身胰岛素敏感性、葡萄糖代谢、肝脂肪变性、血脂异常。我们发现，GluOC 给药通过激活肝 IRβ/PI3K/Akt 通路显著增强了 KKAy 小鼠的胰岛素敏感性，并通过降低 FPI 和 HOMA-IR 指数提高了全身胰岛素敏感性。此外，GluOC 给药通过抑制糖异生和促进 KKAy 小鼠和体外培养的肝细胞中的糖原合成来降低血糖。此外，GluOC 给药剂量依赖性地改善了 KKAy 小鼠的血脂异常和肝脂肪变性，通过抑制肝从头脂肪生成和促进脂肪酸β氧化。这些结果表明，GluOC 有效地增强了肝胰岛素敏感性，改善了 KKAy 小鼠的高血糖，并改善了肝脂肪变性，表明 GluOC 可能是治疗代谢综合征的有前途的药物候选物。
