Obesity is a fibroblast growth factor 21 (FGF21)-resistant state.
OBJECTIVE
Fibroblast growth factor 21 (FGF21) is a key mediator of fatty acid oxidation and lipid metabolism. Pharmacological doses of FGF21 improve glucose tolerance, lower serum free fatty acids, and lead to weight loss in obese mice. Surprisingly, however, FGF21 levels are elevated in obese ob/ob and db/db mice and correlate positively with BMI in humans. However, the expected beneficial effects of endogenous FGF21 to increase glucose tolerance and reduce circulating triglycerides are absent in obesity.


METHODS
To test the hypothesis that obesity is a state of FGF21 resistance, we evaluated the response of obese mice to exogenous FGF21 administration. In doing this, we assessed the impact of diet-induced obesity on FGF21 signaling and resultant transcriptional events in the liver and white adipose tissue. We also analyzed the physiologic impact of FGF21 resistance by assessing serum parameters that are acutely regulated by FGF21.


RESULTS
When obese mice are treated with FGF21, they display both a significantly attenuated signaling response as assessed by extracellular mitogen-activated protein kinase 1 and 2 (ERK1/2) phosphorylation as well as an impaired induction of FGF21 target genes, including cFos and EGR1. These effects were seen in both liver and fat. Similarly, changes in serum parameters such as the decline in glucose and free fatty acids are attenuated in FGF21-treated DIO mice.


CONCLUSIONS
These data demonstrate that DIO mice have increased endogenous levels of FGF21 and respond poorly to exogenous FGF21. We therefore propose that obesity is an FGF21-resistant state.
Fisher
Ffolliott M
FM
Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
Chui
Patricia C
PC
Antonellis
Patrick J
PJ
Bina
Holly A
HA
Kharitonenkov
Alexei
A
Flier
Jeffrey S
JS
Maratos-Flier
Eleftheria
E
D000273:Adipose Tissue / Q000187:drug effects / Q000502:physiology; D000818:Animals; D004351:Drug Resistance; D005346:Fibroblast Growth Factors / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology* / Q000502:physiology; D006801:Humans; D007275:Injections, Intravenous; D008099:Liver / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009765:Obesity / Q000097:blood*; D012333:RNA, Messenger / Q000097:blood / Q000187:drug effects / Q000235:genetics; D011994:Recombinant Proteins / Q000097:blood / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology
D012333:RNA, Messenger; D011994:Recombinant Proteins; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors; D048052:Mitogen-Activated Protein Kinase 3