title: Amelioration of type 2 diabetes by antibody-mediated activation of fibroblast growth factor receptor 1.
abstract: 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.
authors.affiliation: Molecular Biology, Genentech Inc., South San Francisco, CA 94080, USA.
authors.forename: Ai-Luen
authors.initials: AL
authors.lastname: Wu
authors.forename: Ganesh
authors.initials: G
authors.lastname: Kolumam
authors.forename: Scott
authors.initials: S
authors.lastname: Stawicki
authors.forename: Yongmei
authors.initials: Y
authors.lastname: Chen
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Jose
authors.initials: J
authors.lastname: Zavala-Solorio
authors.forename: Khanhky
authors.initials: K
authors.lastname: Phamluong
authors.forename: Bo
authors.initials: B
authors.lastname: Feng
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Scot
authors.initials: S
authors.lastname: Marsters
authors.forename: Lance
authors.initials: L
authors.lastname: Kates
authors.forename: Nicholas
authors.initials: N
authors.lastname: van Bruggen
authors.forename: Maya
authors.initials: M
authors.lastname: Leabman
authors.forename: Anne
authors.initials: A
authors.lastname: Wong
authors.forename: David
authors.initials: D
authors.lastname: West
authors.forename: Howard
authors.initials: H
authors.lastname: Stern
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Luis
authors.forename: Hok Seon
authors.initials: HS
authors.lastname: Kim
authors.forename: Daniel
authors.initials: D
authors.lastname: Yansura
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Peterson
authors.forename: Ellen
authors.initials: E
authors.lastname: Filvaroff
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.forename: Junichiro
authors.initials: J
authors.lastname: Sonoda
mesh_terms: D000273:Adipose Tissue / Q000166:cytology / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D002460:Cell Line; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D005260:Female; D005346:Fibroblast Growth Factors / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051381:Rats; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000378:metabolism*; D014018:Tissue Distribution; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors
chemical_list: D000911:Antibodies, Monoclonal; D017362:Cyclic AMP Response Element-Binding Protein; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D015534:Trans-Activators; D014157:Transcription Factors; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D051496:Receptor, Fibroblast Growth Factor, Type 1