Separating mitogenic and metabolic activities of fibroblast growth factor 19 (FGF19).
FGF19 and FGF21 are distinctive members of the FGF family that function as endocrine hormones. Their potent effects on normalizing glucose, lipid, and energy homeostasis in disease models have made them an interesting focus of research for combating the growing epidemics of diabetes and obesity. Despite overlapping functions, FGF19 and FGF21 have many discrete effects, the most important being that FGF19 has both metabolic and proliferative effects, whereas FGF21 has only metabolic effects. Here we identify the structural determinants dictating differential receptor interactions that explain and distinguish these two physiological functions. We also have generated FGF19 variants that have lost the ability to induce hepatocyte proliferation but that still are effective in lowering plasma glucose levels and improving insulin sensitivity in mice. Our results add valuable insight into the structure-function relationship of FGF19/FGF21 and identify the structural basis underpinning the distinct proliferative feature of FGF19 compared with FGF21. In addition, these studies provide a road map for engineering FGF19 as a potential therapeutic candidate for treating diabetes and obesity.
Wu
Xinle
X
Amgen Inc., South San Francisco, CA 94080, USA.
Ge
Hongfei
H
Lemon
Bryan
B
Vonderfecht
Steven
S
Baribault
Helene
H
Weiszmann
Jennifer
J
Gupte
Jamila
J
Gardner
Jonitha
J
Lindberg
Richard
R
Wang
Zhulun
Z
Li
Yang
Y
D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose; D049109:Cell Proliferation; D003920:Diabetes Mellitus / Q000188:drug therapy; D005346:Fibroblast Growth Factors / Q000502:physiology*; D014644:Genetic Variation; D022781:Hepatocytes / Q000166:cytology*; D007333:Insulin Resistance; D051379:Mice; D009765:Obesity / Q000188:drug therapy; D010446:Peptide Fragments / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D011994:Recombinant Proteins / Q000494:pharmacology
D001786:Blood Glucose; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; C108526:fibroblast growth factor 15, mouse; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors