Research ArticlesMetabolic Disease

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

Science Translational Medicine  14 Dec 2011:
Vol. 3, Issue 113, pp. 113ra126
DOI: 10.1126/scitranslmed.3002669

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Getting at Brown Fat

It’s fun to indulge in holiday cheer, if only a holiday miracle allowed one to avoid the often-linked weight gain. At the molecular level, obesity and type 2 diabetes can be linked by the fibroblast growth factor (FGF) family of proteins and their receptors (FGFRs), with some factors showing disease-reversing capabilities. For instance, overweight, diabetic mice treated with FGF21 regain normal metabolism and lose weight, even without spending hours on a treadmill. However, attempts to use this fat-burning factor in humans have not been successful, owing to poor pharmacokinetics as well as concerns over negative effects of modified FGF21 proteins. In this issue, Wu and colleagues describe an antibody-based FGF21 mimic that circumvents these limitations to overcome metabolic disease in mice.

The authors reasoned that robust drugs that closely mimic FGF21 function would similarly exert antidiabetic effects. Using phage display technology, Wu et al. identified monoclonal antibodies (R1MAbs) that were specifically targeted tissues that play key roles in diabetes and obesity, including adipose (fat) tissue. In contrast to FGF21, which binds several forms of the FGFR throughout the body, the phage-derived R1MAbs bound only to FGFR1—a receptor present in the pancreas and in brown and white adipose tissues. Diabetic mice with high blood sugar (hyperglycemia) were injected once with either R1MAbs or a control antibody. Within 1 week, blood glucose concentrations in the R1MAb-treated mice were normalized and remained at lower levels compared to placebo-treated mice for more than 1 month without reaching dangerously low blood glucose concentrations (hypoglycemia). The R1MAbs also helped the diabetic mice to lose weight, indicating that this antibody agonist of FGFR1 is a dual-action drug for both diabetes and obesity.

Wu et al. also shed light on the mechanism of action of their R1MAbs, showing that they work via FGFR homodimerization in brown adipose tissue. With improved pharmacokinetics over FGF21, in addition to a specific receptor-targeting mechanism, these R1MAbs could enter human clinical trials for diabetes and other obesity-related diseases in the near future. Unfortunately, a miracle drug won’t be available in time for the holidays, so perhaps, this year, opt for the sugar-free egg nog.


  • * These authors contributed equally to this work.