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

被引：138

作者：

Wu, Ai-Luen ^{[1
]}

Kolumam, Ganesh ^{[2
]}

Stawicki, Scott ^{[3
]}

Chen, Yongmei ^{[3
]}

Li, Jun ^{[4
]}

Zavala-Solorio, Jose ^{[2
]}

Phamluong, Khanhky ^{[1
]}

Feng, Bo ^{[1
]}

Li, Li ^{[5
]}

Marsters, Scot ^{[4
]}

Kates, Lance ^{[2
]}

van Bruggen, Nicholas ^{[2
]}

Leabman, Maya ^{[6
]}

Wong, Anne ^{[7
]}

West, David ^{[6
]}

Stern, Howard ^{[8
]}

Luis, Elizabeth ^{[9
]}

Kim, Hok Seon ^{[3
]}

Yansura, Daniel ^{[3
]}

Peterson, Andrew S. ^{[1
]}

Filvaroff, Ellen ^{[4
]}

Wu, Yan ^{[3
]}

Sonoda, Junichiro ^{[1
]}

机构：

[1] Genentech Inc, Mol Biol, San Francisco, CA 94080 USA

[2] Genentech Inc, Biomed Imaging, San Francisco, CA 94080 USA

[3] Genentech Inc, Antibody Engn, San Francisco, CA 94080 USA

[4] Genentech Inc, Mol Oncol, San Francisco, CA 94080 USA

[5] Genentech Inc, Bioinformat & Computat Biol, San Francisco, CA 94080 USA

[6] Genentech Inc, Pharmacokinet & Pharmacodynam Sci, San Francisco, CA 94080 USA

[7] Genentech Inc, Assay & Automat Technol, San Francisco, CA 94080 USA

[8] Genentech Inc, Pathol, San Francisco, CA 94080 USA

[9] Genentech Inc, Prot Chem, San Francisco, CA 94080 USA

来源：

SCIENCE TRANSLATIONAL MEDICINE | 2011年 / 3卷 / 113期

关键词：

PPAR-ALPHA; ENDOCRINE REGULATION; METABOLIC-ACTIVITY; ADIPOSE-TISSUE; BETA-KLOTHO; FGF21; EXPRESSION; FIBROBLAST-GROWTH-FACTOR-21; MICE; IMMUNOTHERAPY;

D O I：

10.1126/scitranslmed.3002669

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页数：10

共 31 条

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