Amelioration of type 2 diabetes by antibody-mediated activation of fibroblast growth factor receptor 1

• Published in: Science translational medicine Vol. 3; no. 113; p. 113ra126
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: United States 14-12-2011
• Subjects: Adipose Tissue - cytology; Adipose Tissue - metabolism; Animals; Antibodies, Monoclonal - therapeutic use; Cell Line; Cyclic AMP Response Element-Binding Protein - metabolism; Diabetes Mellitus, Type 2 - pathology; Diabetes Mellitus, Type 2 - physiopathology; Diabetes Mellitus, Type 2 - therapy; Female; Fibroblast Growth Factors - metabolism; Humans; Male; Mice; Mice, Inbred C57BL; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Rats; Receptor, Fibroblast Growth Factor, Type 1 - genetics; Receptor, Fibroblast Growth Factor, Type 1 - metabolism; Tissue Distribution; Trans-Activators - metabolism; Transcription Factors
• ISSN: 1946-6242
• DOI: 10.1126/scitranslmed.3002669

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-1α (peroxisome proliferator-activated receptor-γ coactivator 1α) 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-1α, and as a compelling target for antibody-based therapy for type 2 diabetes and other obesity-associated disorders.