Department of Pediatrics, University of Alberta, Edmonton, Alberta T6G 2R7, Canada; Department of Metabolism and Aging, Scripps Research Institute, Jupiter, Florida 33458.
Department of Pharmacology and Physiology, Saint Louis University School of Medicine, St. Louis, Missouri 63104.
J Biol Chem. 2019 Sep 6;294(36):13366-13377. doi: 10.1074/jbc.RA119.008967. Epub 2019 Jul 19.
The peptide hormone adropin regulates energy metabolism in skeletal muscle and plays important roles in the regulation of metabolic homeostasis. Besides muscle, the liver has an essential role in regulating glucose homeostasis. Previous studies have reported that treatment of diet-induced obese (DIO) male mice with adropin (the putative secreted domain) reduces fasting blood glucose independently of body weight changes, suggesting that adropin suppresses glucose production in the liver. Here, we explored the molecular mechanisms underlying adropin's effects on hepatic glucose metabolism in DIO mice. Male DIO B6 mice maintained on a high-fat diet received five intraperitoneal injections of adropin (450 nmol/kg/injection) over a 48-h period. We found that adropin enhances major intracellular signaling activities in the liver that are involved in insulin-mediated regulation of glucose homeostasis. Moreover, treatment with adropin alleviated endoplasmic reticulum stress responses and reduced activity of c-Jun N-terminal kinase in the liver, explaining the enhanced activities of hepatic insulin signaling pathways observed with adropin treatment. Furthermore, adropin suppressed cAMP activated protein kinase A (PKA) activities, resulting in reduced phosphorylation of inositol trisphosphate receptor, which mediates endoplasmic reticulum calcium efflux, and of cAMP-responsive element-binding protein, a key transcription factor in hepatic regulation of glucose metabolism. Adropin directly affected liver metabolism, decreasing glucose production and reducing PKA-mediated phosphorylation in primary mouse hepatocytes Our findings indicate that major hepatic signaling pathways contribute to the improved glycemic control achieved with adropin treatment in situations of obesity.
肽激素 adropin 调节骨骼肌能量代谢，并在代谢稳态调节中发挥重要作用。除了肌肉，肝脏在调节葡萄糖稳态方面也起着至关重要的作用。先前的研究报告称，用 adropin（假定的分泌结构域）治疗饮食诱导肥胖（DIO）雄性小鼠可独立于体重变化降低空腹血糖，这表明 adropin 可抑制肝脏的葡萄糖生成。在这里，我们探讨了 adropin 对 DIO 小鼠肝脏葡萄糖代谢影响的分子机制。维持高脂肪饮食的雄性 DIO B6 小鼠在 48 小时内接受了五次腹腔内注射 adropin（450nmol/kg/次）。我们发现，adropin 增强了肝脏中涉及胰岛素介导的葡萄糖稳态调节的主要细胞内信号活性。此外，用 adropin 治疗可减轻内质网应激反应，并降低肝脏中 c-Jun N-末端激酶的活性，这解释了 adropin 治疗观察到的肝脏胰岛素信号通路活性增强。此外，adropin 抑制 cAMP 激活的蛋白激酶 A（PKA）活性，导致肌醇三磷酸受体的磷酸化减少，肌醇三磷酸受体介导内质网钙流出，以及 cAMP 反应元件结合蛋白（调节肝脏葡萄糖代谢的关键转录因子）的磷酸化减少。adropin 直接影响肝脏代谢，降低葡萄糖生成并减少原代小鼠肝细胞中 PKA 介导的磷酸化。我们的研究结果表明，主要的肝信号通路有助于改善肥胖情况下 adropin 治疗的血糖控制。
