Institute for Diabetes and Obesity, Helmholtz Diabetes Center at Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), 85764 Neuherberg, Germany; Division of Metabolic Diseases, Department of Medicine, Technische Universität München, 80333 Munich, Germany; German Center for Diabetes Research (DZD), 85764 Neuherberg, Germany.
Department of Chemistry, Indiana University, Bloomington, IN 47405, USA.
Cell. 2016 Oct 20;167(3):843-857.e14. doi: 10.1016/j.cell.2016.09.014. Epub 2016 Oct 6.
Glucagon and thyroid hormone (T) exhibit therapeutic potential for metabolic disease but also exhibit undesired effects. We achieved synergistic effects of these two hormones and mitigation of their adverse effects by engineering chemical conjugates enabling delivery of both activities within one precisely targeted molecule. Coordinated glucagon and T actions synergize to correct hyperlipidemia, steatohepatitis, atherosclerosis, glucose intolerance, and obesity in metabolically compromised mice. We demonstrate that each hormonal constituent mutually enriches cellular processes in hepatocytes and adipocytes via enhanced hepatic cholesterol metabolism and white fat browning. Synchronized signaling driven by glucagon and T reciprocally minimizes the inherent harmful effects of each hormone. Liver-directed T action offsets the diabetogenic liability of glucagon, and glucagon-mediated delivery spares the cardiovascular system from adverse T action. Our findings support the therapeutic utility of integrating these hormones into a single molecular entity that offers unique potential for treatment of obesity, type 2 diabetes, and cardiovascular disease.
胰高血糖素和甲状腺激素 (T) 在代谢性疾病方面具有治疗潜力，但也具有不良作用。我们通过工程化学缀合物实现了这两种激素的协同作用，并减轻了它们的不良反应，从而能够在一个精确靶向的分子内同时传递两种活性。协调的胰高血糖素和 T 作用协同纠正高脂血症、脂肪性肝炎、动脉粥样硬化、葡萄糖不耐受和代谢受损小鼠的肥胖症。我们证明，每种激素成分都通过增强肝脏胆固醇代谢和白色脂肪褐变使肝细胞和脂肪细胞中的细胞过程更加丰富。胰高血糖素和 T 驱动的同步信号通过相互最小化每种激素固有的有害作用。肝脏定向的 T 作用抵消了胰高血糖素的致糖尿病作用，而胰高血糖素介导的传递使心血管系统免受 T 作用的不良影响。我们的研究结果支持将这些激素整合到单个分子实体中的治疗效用，这为肥胖症、2 型糖尿病和心血管疾病的治疗提供了独特的潜力。
