Amelioration of Type 2 Diabetes by Antibody-Mediated Activation of Fibroblast Growth Factor Receptor 1
Amelioration of Type 2 Diabetes by Antibody-Mediated Activation of Fibroblast Growth Factor Receptor 1
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DOI：
10.1126/scitranslmed.3002669
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发表时间：
2011-12-14
影响因子：
17.1
通讯作者：
Sonoda, Junichiro
中科院分区：
文献类型：
--
作者：
Wu, Ai-Luen;Kolumam, Ganesh;Sonoda, Junichiro
重组成纤维细胞生长因子21 （FGF21）用于治疗2型糖尿病和其他与肥胖相关的疾病的临床应用已被提出；然而，由于其药代动力学较差，其临床开发一直具有挑战性。在这里，我们描述了一种替代的抗糖尿病策略，使用激动性抗fgfr1 （FGF受体1）抗体（r1mab），模拟FGF21的代谢作用。向肥胖糖尿病小鼠单次注射R1MAb可诱导急性和持续改善高血糖，同时显著改善高胰岛素血症、高脂血症和肝纤维化。R1MAb在脂肪组织中激活了丝裂原激活的蛋白激酶途径，但在肝脏中没有激活，FGF21和R1MAb都没有改善脂肪萎缩小鼠的葡萄糖清除，这表明脂肪组织在观察到的代谢作用中发挥了核心作用。在棕色脂肪组织中，FGF21和R1MAb均诱导了CREB（环腺苷5′-单磷酸反应元件结合蛋白）的磷酸化，以及PGC-1 α（过氧化物酶体增殖体激活受体- γ辅激活因子1 α）和氧化代谢相关下游基因的mRNA表达。总之，我们提出脂肪组织中的FGFR1作为FGF21的主要功能受体，作为PGC-1 α的上游调节因子，并且作为基于抗体的2型糖尿病和其他肥胖相关疾病治疗的引人注目的靶点。
Clinical use of recombinant fibroblast growth factor 21 (FGF21) for the treatment of type 2 diabetes and other disorders linked to obesity has been proposed; however, its clinical development has been challenging owing to its poor pharmacokinetics. Here, we describe an alternative antidiabetic strategy using agonistic anti-FGFR1 (FGF receptor 1) antibodies (R1MAbs) that mimic the metabolic effects of FGF21. A single injection of R1MAb into obese diabetic mice induced acute and sustained amelioration of hyperglycemia, along with marked improvement in hyperinsulinemia, hyperlipidemia, and hepatosteatosis. R1MAb activated the mitogen-activated protein kinase pathway in adipose tissues, but not in liver, and neither FGF21 nor R1MAb improved glucose clearance in lipoatrophic mice, which suggests that adipose tissues played a central role in the observed metabolic effects. In brown adipose tissues, both FGF21 and R1MAb induced phosphorylation of CREB (cyclic adenosine 5'-monophosphate response element-binding protein), and mRNA expression of PGC-1 alpha (peroxisome proliferator-activated receptor-gamma coactivator 1 alpha) and the downstream genes associated with oxidative metabolism. Collectively, we propose FGFR1 in adipose tissues as a major functional receptor for FGF21, as an upstream regulator of PGC-1 alpha, and as a compelling target for antibody-based therapy for type 2 diabetes and other obesity-associated disorders.