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Transgenic Mice Expressing Human Fibroblast Growth Factor-19 Display Increased Metabolic Rate and Decreased Adiposity

Departments of Molecular Biology (E.T., L.F., L.J., B.H., X.H., M.R., T.A.S.), Automation and Assay Technology (J.P.S., S.P.T.), Cardiovascular Research (L.P.-B.) and Pathology (D.F.), Genentech, Inc., South San Francisco, California 94080

Address all correspondence and requests for reprints to: Timothy A. Stewart, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080. E-mail: . tas{at}gene.com

The fibroblast growth factors (FGFs), and the corresponding receptors, are implicated in more than just the regulation of epithelial cell proliferation and differentiation. Specifically, FGF23 is a regulator of serum inorganic phosphate levels, and mice deficient in FGF receptor-4 have altered cholesterol metabolism. The recently described FGF19 is unusual in that it is nonmitogenic and appears to interact only with FGF receptor-4. Here, we report that FGF19 transgenic mice had a significant and specific reduction in fat mass that resulted from an increase in energy expenditure. Further, the FGF19 transgenic mice did not become obese or diabetic on a high fat diet. The FGF19 transgenic mice had increased brown adipose tissue mass and decreased liver expression of acetyl coenzyme A carboxylase 2, providing two mechanisms by which FGF19 may increase energy expenditure. Consistent with the reduction in expression of acetyl CoA carboxylase 2, liver triglyceride levels were reduced.

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