Fibroblast growth factor 21 reverses hepatic steatosis, increases energy expenditure, and improves insulin sensitivity in diet-induced obese mice.
OBJECTIVE
Fibroblast growth factor 21 (FGF21) has emerged as an important metabolic regulator of glucose and lipid metabolism. The aims of the current study are to evaluate the role of FGF21 in energy metabolism and to provide mechanistic insights into its glucose and lipid-lowering effects in a high-fat diet-induced obesity (DIO) model.


METHODS
DIO or normal lean mice were treated with vehicle or recombinant murine FGF21. Metabolic parameters including body weight, glucose, and lipid levels were monitored, and hepatic gene expression was analyzed. Energy metabolism and insulin sensitivity were assessed using indirect calorimetry and hyperinsulinemic-euglycemic clamp techniques.


RESULTS
FGF21 dose dependently reduced body weight and whole-body fat mass in DIO mice due to marked increases in total energy expenditure and physical activity levels. FGF21 also reduced blood glucose, insulin, and lipid levels and reversed hepatic steatosis. The profound reduction of hepatic triglyceride levels was associated with FGF21 inhibition of nuclear sterol regulatory element binding protein-1 and the expression of a wide array of genes involved in fatty acid and triglyceride synthesis. FGF21 also dramatically improved hepatic and peripheral insulin sensitivity in both lean and DIO mice independently of reduction in body weight and adiposity.


CONCLUSIONS
FGF21 corrects multiple metabolic disorders in DIO mice and has the potential to become a powerful therapeutic to treat hepatic steatosis, obesity, and type 2 diabetes.
Xu
Jing
J
Department of Metabolic Disorders, Amgen, Thousand Oaks, California, USA. jingx@amgen.com
Lloyd
David J
DJ
Hale
Clarence
C
Stanislaus
Shanaka
S
Chen
Michelle
M
Sivits
Glenn
G
Vonderfecht
Steven
S
Hecht
Randy
R
Li
Yue-Sheng
YS
Lindberg
Richard A
RA
Chen
Jin-Long
JL
Jung
Dae Young
DY
Zhang
Zhiyou
Z
Ko
Hwi-Jin
HJ
Kim
Jason K
JK
Véniant
Murielle M
MM
D050154:Adiposity / Q000187:drug effects; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D015153:Blotting, Western; D001835:Body Weight / Q000187:drug effects; D002151:Calorimetry; D004041:Dietary Fats / Q000008:administration & dosage; D004734:Energy Metabolism / Q000187:drug effects*; D005234:Fatty Liver / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D005941:Glucokinase / Q000235:genetics / Q000378:metabolism; D015309:Glucose Clamp Technique; D007328:Insulin / Q000097:blood; D007333:Insulin Resistance / Q000502:physiology*; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000188:drug therapy* / Q000209:etiology / Q000503:physiopathology; D011770:Pyruvate Kinase / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction
D001786:Blood Glucose; D004041:Dietary Fats; D007328:Insulin; D008055:Lipids; D011994:Recombinant Proteins; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D005941:Glucokinase; D011770:Pyruvate Kinase