Amgen Inc., South San Francisco, CA 94080, USA.
Proc Natl Acad Sci U S A. 2010 Aug 10;107(32):14158-63. doi: 10.1073/pnas.1009427107. Epub 2010 Jul 26.
FGF19 and FGF21 are distinctive members of the FGF family that function as endocrine hormones. Their potent effects on normalizing glucose, lipid, and energy homeostasis in disease models have made them an interesting focus of research for combating the growing epidemics of diabetes and obesity. Despite overlapping functions, FGF19 and FGF21 have many discrete effects, the most important being that FGF19 has both metabolic and proliferative effects, whereas FGF21 has only metabolic effects. Here we identify the structural determinants dictating differential receptor interactions that explain and distinguish these two physiological functions. We also have generated FGF19 variants that have lost the ability to induce hepatocyte proliferation but that still are effective in lowering plasma glucose levels and improving insulin sensitivity in mice. Our results add valuable insight into the structure-function relationship of FGF19/FGF21 and identify the structural basis underpinning the distinct proliferative feature of FGF19 compared with FGF21. In addition, these studies provide a road map for engineering FGF19 as a potential therapeutic candidate for treating diabetes and obesity.
成纤维细胞生长因子 19（FGF19）和成纤维细胞生长因子 21（FGF21）是成纤维细胞生长因子家族中具有独特功能的成员，它们作为内分泌激素发挥作用。它们在疾病模型中对葡萄糖、脂质和能量稳态的正常化具有强大的作用，这使它们成为研究治疗糖尿病和肥胖症这两种日益流行疾病的一个有趣焦点。尽管 FGF19 和 FGF21 具有重叠的功能，但它们具有许多不同的作用，最重要的是，FGF19 既有代谢作用又有增殖作用，而 FGF21 只有代谢作用。在这里，我们确定了决定不同受体相互作用的结构决定因素，这些因素解释和区分了这两种生理功能。我们还生成了失去诱导肝细胞增殖能力但仍能有效降低小鼠血糖水平和改善胰岛素敏感性的 FGF19 变体。我们的研究结果为 FGF19/FGF21 的结构-功能关系提供了有价值的见解，并确定了 FGF19 与 FGF21 相比具有独特增殖特征的结构基础。此外，这些研究为工程 FGF19 作为治疗糖尿病和肥胖症的潜在治疗候选物提供了路线图。
