The Klotho proteins, αKlotho and βKlotho, are essential components of endocrine fibroblast growth factor (FGF) receptor complexes, as they are required for the high-affinity binding of FGF19, FGF21 and FGF23 to their cognate FGF receptors (FGFRs). Collectively, these proteins form a unique endocrine system that governs multiple metabolic processes in mammals. FGF19 is a satiety hormone that is secreted from the intestine on ingestion of food and binds the βKlotho–FGFR4 complex in hepatocytes to promote metabolic responses to feeding. By contrast, under fasting conditions, the liver secretes the starvation hormone FGF21, which induces metabolic responses to fasting and stress responses through the activation of the hypothalamus–pituitary–adrenal axis and the sympathetic nervous system following binding to the βKlotho–FGFR1c complex in adipocytes and the suprachiasmatic nucleus, respectively. Finally, FGF23 is secreted by osteocytes in response to phosphate intake and binds to αKlotho–FGFR complexes, which are expressed most abundantly in renal tubules, to regulate mineral metabolism. Growing evidence suggests that the FGF–Klotho endocrine system also has a crucial role in the pathophysiology of ageing-related disorders, including diabetes, cancer, arteriosclerosis and chronic kidney disease. Therefore, targeting the FGF–Klotho endocrine axes might have therapeutic benefit in multiple systems; investigation of the crystal structures of FGF–Klotho–FGFR complexes is paving the way for the development of drugs that can regulate these axes.

Klotho 蛋白 αKlotho 和 βKlotho 是内分泌成纤维细胞生长因子 (FGF) 受体复合物的重要组成部分，因为它们是 FGF19、FGF21 和 FGF23 与其同源 FGF 受体 (FGFR) 高亲和力结合所必需的。总的来说，这些蛋白质形成了一个独特的内分泌系统，控制着哺乳动物的多种代谢过程。FGF19 是一种饱腹感激素，在摄入食物时从肠道分泌，并结合肝细胞中的 βKlotho-FGFR4 复合物以促进对进食的代谢反应。相比之下，在禁食条件下，肝脏会分泌饥饿激素 FGF21，它通过分别与脂肪细胞和视交叉上核中的βKlotho-FGFR1c复合物结合后激活下丘脑-垂体-肾上腺轴和交感神经系统来诱导对禁食和应激反应的代谢反应。最后，骨细胞响应磷酸盐摄入而分泌 FGF23，并与在肾小管中表达最多的 αKlotho-FGFR 复合物结合，以调节矿物质代谢。越来越多的证据表明，FGF-Klotho 内分泌系统在衰老相关疾病（包括糖尿病、癌症、动脉硬化和慢性肾病）的病理生理学中也起着至关重要的作用。因此，靶向 FGF-Klotho 内分泌轴可能在多个系统中具有治疗益处；