Details

Autor(en) / Beteiligte

• 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

Titel

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

Ist Teil von

• Science translational medicine, 2011-12, Vol.3 (113), p.113ra126

Ort / Verlag

United States

Erscheinungsjahr

2011

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.