Department of Endocrinology and Diabetes, Xiamen Diabetes Institute, Fujian Key Laboratory of Translational Research for Diabetes, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, 361003, China.
Department of Public Health and Medical Technology, Xiamen Medical College, Xiamen, 361023, China.
Sci Rep. 2022 Jul 27;12(1):12869. doi: 10.1038/s41598-022-17000-w.
Obesity is an expanding global public health problem and a leading cause of metabolic disorders. The hepatokine Fetuin B participates in regulating insulin resistance, glucose metabolism and liver steatosis. However, the mechanism underlying Fetuin B activation remains unclear. Our previous population-based study demonstrated a significant association between serum Fetuin B and body fat mass in an obese population, which indicates its potential in mediating obesity-related metabolic disorders. In the present study, we further revealed a significant correlation between Fetuin B and leptin, the classic adipokine released by expanding adipose tissue, in this obese population. Consistently, elevated Fetuin B and leptin levels were confirmed in diet-induced obese mice. Furthermore, an in vitro study demonstrated that the leptin signalling pathway directly activated the transcription and expression of Fetuin B in primary hepatocytes and AML12 cells in a STAT3-dependent manner. STAT3 binds to the response elements on FetuB promoter to directly activate FetuB transcription. Finally, the mediating effect of Fetuin B in insulin resistance induced by leptin was confirmed according to mediation analysis in this obese population. Therefore, our study identifies leptin-STAT3 as an upstream signalling pathway that activates Fetuin B and provides new insights into the pathogenic mechanisms of obesity-related metabolic disorders.
肥胖是一个全球性的公共健康问题，也是代谢紊乱的主要原因。肝分泌素 B 参与调节胰岛素抵抗、葡萄糖代谢和肝脂肪变性。然而，肝分泌素 B 激活的机制尚不清楚。我们之前的基于人群的研究表明，在肥胖人群中，血清肝分泌素 B 与体脂肪量之间存在显著关联，这表明其在介导肥胖相关代谢紊乱方面具有潜力。在本研究中，我们进一步揭示了在肥胖人群中，肝分泌素 B 与瘦素之间存在显著相关性，瘦素是扩张的脂肪组织释放的经典脂肪因子。一致的是，在饮食诱导的肥胖小鼠中证实了升高的肝分泌素 B 和瘦素水平。此外，一项体外研究表明，瘦素信号通路通过 STAT3 依赖性方式直接激活原代肝细胞和 AML12 细胞中肝分泌素 B 的转录和表达。STAT3 结合到 FetuB 启动子上的反应元件，直接激活 FetuB 转录。最后，根据肥胖人群中的中介分析，证实了肝分泌素 B 在瘦素诱导的胰岛素抵抗中的中介作用。因此，我们的研究确定了瘦素-STAT3 作为激活肝分泌素 B 的上游信号通路，并为肥胖相关代谢紊乱的发病机制提供了新的见解。
