STM：FGF21有望成为糖尿病治疗新靶点

Amelioration of Type 2 Diabetes by Antibody-Mediated Activation of Fibroblast Growth Factor Receptor 1

Wu, Ai-Luen; Kolumam, Ganesh; Stawicki, Scott; Chen, Yongmei; Li, Jun; Zavala-Solorio, Jose; Phamluong, Khanhky; Feng, Bo; Li, Li; Marsters, Scot; Kates, Lance; van Bruggen, Nicholas; Leabman, Maya; Wong, Anne; West, David; Stern, Howard; Luis, Elizabeth; Kim, Hok Seon; Yansura, Daniel; Peterson, Andrew S.; Filvaroff, Ellen; Wu, Yan; Sonoda, Junichiro

Clinical use of recombinant fibroblast growth factor 21 (FGF21) for the treatment of type 2 diabetes and other disorders linkedto 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 mimicthe metabolic effects of FGF21. A single injection of R1MAb into obese diabetic mice induced acute and sustained ameliorationof hyperglycemia, along with marked improvement in hyperinsulinemia, hyperlipidemia, and hepatosteatosis. R1MAb activatedthe mitogen-activated protein kinase pathway in adipose tissues, but not in liver, and neither FGF21 nor R1MAb improved glucoseclearance 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 responseelement–binding protein), and mRNA expression of PGC-1α (peroxisome proliferator–activated receptor-γ coactivator 1α) andthe downstream genes associated with oxidative metabolism. Collectively, we propose FGFR1 in adipose tissues as a major functionalreceptor for FGF21, as an upstream regulator of PGC-1α, and as a compelling target for antibody-based therapy for type 2 diabetesand other obesity-associated disorders.