FGF-21 as a novel metabolic regulator
Alexei Kharitonenkov, … , S. Richard Jaskunas, Armen B. Shanafelt
Alexei Kharitonenkov, … , S. Richard Jaskunas, Armen B. Shanafelt
Published June 1, 2005
Citation Information: J Clin Invest. 2005;115(6):1627-1635. https://doi.org/10.1172/JCI23606.
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Research Article Metabolism

FGF-21 as a novel metabolic regulator

Abstract

Diabetes mellitus is a major health concern, affecting more than 5% of the population. Here we describe a potential novel therapeutic agent for this disease, FGF-21, which was discovered to be a potent regulator of glucose uptake in mouse 3T3-L1 and primary human adipocytes. FGF-21–transgenic mice were viable and resistant to diet-induced obesity. Therapeutic administration of FGF-21 reduced plasma glucose and triglycerides to near normal levels in both ob/ob and db/db mice. These effects persisted for at least 24 hours following the cessation of FGF-21 administration. Importantly, FGF-21 did not induce mitogenicity, hypoglycemia, or weight gain at any dose tested in diabetic or healthy animals or when overexpressed in transgenic mice. Thus, we conclude that FGF-21, which we have identified as a novel metabolic factor, exhibits the therapeutic characteristics necessary for an effective treatment of diabetes.

Authors

Alexei Kharitonenkov, Tatiyana L. Shiyanova, Anja Koester, Amy M. Ford, Radmila Micanovic, Elizabeth J. Galbreath, George E. Sandusky, Lisa J. Hammond, Julie S. Moyers, Rebecca A. Owens, Jesper Gromada, Joseph T. Brozinick, Eric D. Hawkins, Victor J. Wroblewski, De-Shan Li, Farrokh Mehrbod, S. Richard Jaskunas, Armen B. Shanafelt

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FGF-21 injection studies in rodents. The values (± SE) shown are the ave...
FGF-21 injection studies in rodents. The values (± SE) shown are the average of the measurements of at least 5 animals in a group. *P < 0.05, **P < 0.02, and #P < 0.001 compared with vehicle control. Fed blood glucose (A) and triglyceride levels (B) in ob/ob mice treated with FGF-21. FGF-21 was administered once daily, and blood glucose and triglyceride levels were measured 1 hour after the last injection. (C) Fed blood glucose levels in db/db mice at days 18 and 46 during 8-week constant-infusion study. Mice were infused s.c. with 11 μg/kg/h FGF-21 using ALZET minipumps. (D and E) FGF-21 lowers glucose in obese ZDF rats and does not induce hypoglycemia in lean ZDF rats. Fed blood glucose levels were measured in obese (D) and lean (E) ZDF rats that were administered s.c. twice daily with FGF-21, Humulin, or vehicle at indicated total daily doses for 1 week. (F) FGF-21 induces extended lowering of fed blood glucose in ob/ob mice. FGF-21 was administered once daily for 7 days, and blood glucose levels were measured after the last injection at indicated time points. (G and H) FGF-21 affects insulin levels (G) and glucose disposal (H) during OGTT in ob/ob mice. At indicated time points, blood samples were obtained for glucose and insulin measurements.