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

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Ai-Luen Wu1, Ganesh Kolumam, Scott Stawicki

  • 1Molecular Biology, Genentech Inc., South San Francisco, CA 94080, USA.

Science Translational Medicine
|December 17, 2011
PubMed

Insights

Agonistic antibodies targeting FGF receptor 1 (FGFR1) offer a new approach for type 2 diabetes treatment. These antibodies mimic fibroblast growth factor 21 (FGF21) effects, improving metabolic parameters in obese diabetic mice.

Area of Science:

  • Metabolic disorders
  • Endocrinology
  • Immunotherapy

Background:

  • Recombinant fibroblast growth factor 21 (FGF21) shows promise for type 2 diabetes but faces pharmacokinetic challenges.
  • Obesity-associated disorders, including type 2 diabetes, require novel therapeutic strategies.

Purpose of the Study:

  • To develop an alternative antidiabetic strategy using agonistic anti-FGFR1 antibodies (R1MAbs) that mimic FGF21's metabolic effects.
  • To investigate the role of adipose tissue and FGFR1 in mediating FGF21's metabolic actions.

Main Methods:

  • Administration of R1MAbs to obese diabetic mice.
  • Analysis of metabolic parameters including hyperglycemia, hyperinsulinemia, hyperlipidemia, and hepatosteatosis.
  • Investigation of signaling pathways (MAPK, CREB) and gene expression (PGC-1α) in adipose tissues and liver.
  • Assessment of FGF21 and R1MAb efficacy in lipoatrophic mice.

Main Results:

  • A single R1MAb injection led to sustained improvements in hyperglycemia, hyperinsulinemia, hyperlipidemia, and hepatosteatosis in obese diabetic mice.
  • R1MAb activated the MAPK pathway in adipose tissue but not liver.
  • FGFR1 activation in brown adipose tissue by FGF21 and R1MAb increased CREB phosphorylation and PGC-1α expression, enhancing oxidative metabolism.
  • Neither FGF21 nor R1MAb improved glucose clearance in lipoatrophic mice, highlighting the critical role of adipose tissue.

Conclusions:

  • FGFR1 in adipose tissue is a key functional receptor for FGF21 and an upstream regulator of PGC-1α.
  • R1MAbs represent a promising antibody-based therapeutic strategy for type 2 diabetes and other obesity-related metabolic disorders.

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