Obesity Is a Fibroblast Growth Factor 21
(FGF21)-Resistant State
ffolliott M. Fisher,1 Patricia C. Chui,1 Patrick J. Antonellis,1 Holly A. Bina,2 Alexei Kharitonenkov,2
Jeffrey S. Flier,1 and Eleftheria Maratos-Flier1
OBJECTIVE—Fibroblast growth factor 21 (FGF21) is a key
mediator of fatty acid oxidation and lipid metabolism. Pharma-
cological 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.
RESEARCH DESIGN AND METHODS—To test the hypothe-
sis 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. Diabetes 59:2781–2789, 2010
Fibroblast growth factor 21 (FGF21) has emergedas a key mediator of the fasted state and contrib-utes to regulating lipolysis in white adipose tis-sue (WAT) (1–3) as well as increasing substrate
utilization by increasing fatty acid oxidation in the liver
(4). In addition, other studies have found that FGF21
increases insulin-independent glucose uptake in 3T3L1
adipocytes. Treatment of ob/ob mice with pharmacologic
doses of FGF21 leads to improved glucose tolerance and
reduced serum triglycerides (5). Subsequent studies have
reported that chronic treatment of diet-induced obese
(DIO) mice with FGF21 also leads to an improved meta-
bolic profile (6,7). A similar effect has been reported in
diabetic monkeys (8). Consistent with its actions on lipid
oxidation in the liver and lipolysis in WAT, mice lacking
FGF21 demonstrate a phenotype of mild obesity and an
atypical response to feeding of a ketogenic diet (9).
FGF21 binds to isoforms of FGF receptor 1, 2, 3, and 4
(10–12) in the presence of a critical co-receptor termed
“
Klotho.” This leads to rapid dimerization and autophos-
phorylation of the FGF receptor, which recruits and
activates the ras/raf MAP kinase signaling cascade. This
ultimately leads to activation of extracellular mitogen-
activated protein kinase 1 and 2 (ERK1/2), which translo-
cates to the nucleus and activates a subset of transcription
factors. Part of this process is activation of transcription
factors that regulate elements of the serum response,
leading to induction of immediate early gene expression. It
is now well established that exogenous treatment of
FGF21 leads to a rapid induction of ERK1/2 phosphoryla-
tion in adipose tissue depots (13–15). In addition, our lab
and others (15) have found similar results in the liver.
The wealth of data on this peptide suggests that FGF21
may be an excellent candidate molecule for therapeutic
treatment of diabetes and cardiovascular disease associ-
ated with obesity. It is therefore surprising that in obese
states, which are typically associated with glucose intol-
erance, serum FGF21 levels are high. In fact, in both
rodent diet-induced obese (DIO) (16) and in genetically
obese db/db (17) and ob/ob mice, FGF21 expression is
increased in WAT and liver (18). In addition, in humans,
circulating FGF21 levels were found to correlate positively
with BMI (17,19). This increase in circulating levels is seen
in the context of impaired glucose tolerance and increased
accumulation of lipid in the liver. This suggests that, in the
obese state, FGF21 fails to exert its expected effects on
glucose homeostasis and lipid oxidation. Consistent with
this, a recent article found that acute continuous infusion
of FGF21 to control mice leads to reduced hepatic glucose
output and increased insulin sensitivity while having no
effect on obese ob/ob mice (20). These data have led us to
hypothesize that obesity is an FGF21-resistant state.
To test this hypothesis, we examined the effects of
exogenous FGF21 on signal transduction and gene
expression in the liver and WAT of DIO and lean mice.
We found that DIO mice display a severely impaired
signaling response to FGF21 and an attenuated effect to
induce expression of target genes. In addition, low-dose
FGF21 treatment was associated with an impaired im-
provement in serum parameters in the DIO mice. These
findings are consistent with obesity being an FGF21-
resistant state.
From the 1Department of Medicine, Beth Israel Deaconess Medical Center,
Harvard Medical School, Boston, Massachusetts; and 2Lilly Research Lab-
oratories, Indianapolis, Indiana.
Corresponding author: Eleftheria Maratos-Flier, emaratos@bidmc.harvard.
edu.
Received 8 February 2010 and accepted 14 July 2010. Published ahead of print
at http://diabetes.diabetesjournals.org on 3 August 2010. DOI: 10.2337/
db10-0193.
© 2010 by the American Diabetes Association. Readers may use this article as
long as the work is properly cited, the use is educational and not for profit,
and the work is not altered. See http://creativecommons.org/licenses/by
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ORIGINAL ARTICLE
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