Growth differentiation factor 15 (GDF15) is a member of the TGFβ superfamily whose expression is increased in response to cellular stress and disease as well as by metformin. Elevations in GDF15 reduce food intake and body mass in animal models through binding to glial cell-derived neurotrophic factor family receptor alpha-like (GFRAL) and the recruitment of the receptor tyrosine kinase RET in the hindbrain. This effect is largely independent of other appetite-regulating hormones (for example, leptin, ghrelin or glucagon-like peptide 1). Consistent with an important role for the GDF15–GFRAL signalling axis, some human genetic studies support an interrelationship with human obesity. Furthermore, findings in both mice and humans have shown that metformin and exercise increase circulating levels of GDF15. GDF15 might also exert anti-inflammatory effects through mechanisms that are not fully understood. These unique and distinct mechanisms for suppressing food intake and inflammation makes GDF15 an appealing candidate to treat many metabolic diseases, including obesity, type 2 diabetes mellitus, non-alcoholic fatty liver disease, cardiovascular disease and cancer cachexia. Here, we review the mechanisms regulating GDF15 production and secretion, GDF15 signalling in different cell types, and how GDF15-targeted pharmaceutical approaches might be effective in the treatment of metabolic diseases.

生长分化因子 15 (GDF15) 是 TGFβ 超家族的成员，其表达会随着细胞应激和疾病以及二甲双胍而增加。GDF15 的升高通过与神经胶质细胞衍生的神经营养因子家族受体 α 样 (GFRAL) 结合并在后脑中募集受体酪氨酸激酶 RET，从而减少动物模型中的食物摄入量和体重。这种效果在很大程度上独立于其他食欲调节激素（例如，瘦素、生长素释放肽或胰高血糖素样肽 1）。与 GDF15-GFRAL 信号轴的重要作用一致，一些人类遗传研究支持与人类肥胖的相互关系。此外，小鼠和人类的研究结果表明，二甲双胍和运动会增加 GDF15 的循环水平。GDF15 也可能通过尚未完全了解的机制发挥抗炎作用。这些独特而独特的抑制食物摄入和炎症的机制使 GDF15 成为治疗许多代谢疾病的有吸引力的候选者，包括肥胖、2 型糖尿病、非酒精性脂肪肝、心血管疾病和癌症恶病质。在这里，我们回顾了调节 GDF15 产生和分泌的机制、不同细胞类型中的 GDF15 信号传导，以及 GDF15 靶向药物方法如何有效治疗代谢疾病。非酒精性脂肪肝、心血管疾病和癌症恶病质。在这里，我们回顾了调节 GDF15 产生和分泌的机制、不同细胞类型中的 GDF15 信号传导，以及 GDF15 靶向药物方法如何有效治疗代谢疾病。非酒精性脂肪肝、心血管疾病和癌症恶病质。在这里，我们回顾了调节 GDF15 产生和分泌的机制、不同细胞类型中的 GDF15 信号传导，以及 GDF15 靶向药物方法如何有效治疗代谢疾病。