Endocrine fibroblast growth factors
15/19 and 21: from feast to famine
Matthew J. Potthoff,1,2Steven A. Kliewer,1,3,4,5and David J. Mangelsdorf1,2,4
1Department of Pharmacology,2Howard Hughes Medical Institute,
Southwestern Medical Center, Dallas, Texas 75390, USA
3Department of Molecular Biology, University of Texas
We review the physiology and pharmacology of two
atypical fibroblast growth factors (FGFs)—FGF15/19 and
FGF21—that can function as hormones. Both FGF15/19
and FGF21 act on multiple tissues to coordinate carbohy-
drate and lipid metabolism in response to nutritional status.
Whereas FGF15/19 is secreted from the small intestine in
response to feeding and has insulin-like actions, FGF21 is
secreted from the liver in response to extended fasting and
has glucagon-like effects. FGF21 also acts in an autocrine
fashion in several tissues, including adipose. The phar-
macological actions of FGF15/19 and FGF21 make them
attractive drug candidates for treating metabolic disease.
The discovery of hormones such as insulin and glucagon
that regulate metabolism has a long and storied history.
The field of endocrinology continues to be invigorated by
the discovery of new metabolic hormones. Among the
relatively recent additions are three fibroblast growth
factors (FGFs), termed FGF15/19, FGF21, and FGF23.
(FGF15 and FGF19 are the mouse and human orthologs,
respectively, which we refer to as FGF15/19 unless specif-
ically referring to one species or the other.) In contrast to
most FGFs, which act in an autocrine or paracrine fashion,
the three ‘‘endocrine FGFs’’ can be released into the blood-
stream to act throughout the body. While the fundamental
role that FGF23 plays in regulating phosphate metabolism
has been known for more than a decade (White et al. 2000;
Shimada et al. 2001),the discovery of FGF15/19 andFGF21
and their wide-ranging effects on carbohydrate and lipid
metabolism has been more recent. This review focuses on
FGF15/19 and FGF21.
Most FGF family members mediate their effects by
binding to FGF receptors (FGFRs) on the cell surface
(Beenken and Mohammadi 2009). FGFRs are receptor
tyrosine kinases encoded by four genes (FGFR1–4), with
alternate splicing of FGFR1–3 yielding two isoforms (‘‘b’’
and ‘‘c’’) that differ in their extracellular domains and
ligand-binding profiles. Typically, FGFs require an addi-
tional interaction with heparan sulfate glycosaminoglycans
in the extracellular matrix to activate their receptors.
FGF binding to the FGFR/heparan sulfate complex causes
receptor dimerization and autophosphorylation and the
subsequent phosphorylation and activation of downstream
substrates, including FGFR substrate 2a, and MAP kinases
such as ERK1 and ERK2 (Beenken and Mohammadi 2009).
Unlike conventional FGFs, the endocrine FGFs interact
only weakly with heparan sulfate. As a consequence, they
are able to diffuse away from their cells of origin and enter
circulation (Goetz et al. 2007). To compensate for their
inability to interact with heparan sulfate, the endocrine
FGFs require members of the Klotho family of proteins
for high-affinity receptor binding (Kurosu and Kuro 2009).
and lactase-like. All three are single-pass transmembrane
proteins that interact with FGFRs to enable selective bind-
ing of the three endocrine FGFs. a-Klotho serves as the
coreceptor for FGF23, and b-Klotho serves as the corecep-
tor for FGF15/19 and FGF21 (Kurosu et al. 2006, 2007;
Urakawa et al. 2006; Ogawa et al. 2007; Wu et al. 2007;
Kharitonenkov et al. 2008). FGF15/19 can also signal
through lactase-like/FGFR complexes (Fon Tacer et al.
2010). While the FGFRs have very broad tissue distribu-
tions, expression of the Klotho proteins is more restricted
(Fon Tacer et al. 2010). Thus, the sites of action for the
endocrine FGFs are largely dictated by the presence or
absence of the Klotho proteins.
Discovery and role in regulating bile acid homeostasis
FGF19 was originally identified in a screen for novel FGFs
in the fetal brain (Nishimura et al. 1999). While most
FGFs are highly conserved between rodents and humans,
sharing >90% amino acid identity, FGF19 shares only
;50%aminoacididentitywithits rodentortholog, FGF15
(McWhirter et al. 1997). However, the Fgf15 and FGF19
genes are syntenic (Katoh 2003) and havesimilar tissue ex-
pression profiles (e.g., small intestine and fetal brain)
(Nishimura et al. 1999; Xie et al. 1999; Gimeno et al. 2002;
Inagakiet al. 2005;Krejci etal.2007; FonTacer et al. 2010),
and their protein products elicit similar effects on gene
expression and metabolic parameters in mice (Inagaki
et al. 2005; Potthoff et al. 2011). During mouse embryo-
[Keywords: FGF15; FGF19; FGF21; bile acids; obesity; diabetes]
4These authors contributed equally to this work.
Article published online ahead of print. Article and publication date are
online at http://www.genesdev.org/cgi/doi/10.1101/gad.184788.111.
312GENES & DEVELOPMENT 26:312–324 ? 2012 by Cold Spring Harbor Laboratory Press ISSN 0890-9369/12; www.genesdev.org
genesis, Fgf15 has a complex and dynamic pattern of
expression in the CNS (McWhirter et al. 1997; Gimeno
et al. 2002, 2003; Ishibashi and McMahon 2002). This
includes prominent expression in secondary organizers of
the brain, which induce and maintain the regional char-
acteristics of the surrounding neuroepithelium. Studies
done with FGF15 knockout (KO) embryos show that
FGF15 suppresses proliferation and promotes differentia-
tion of neural precursors (Borello et al. 2008; Fischer et al.
2011). Fgf15 is not detected in the adult CNS (Fon Tacer
et al. 2010).
A primary function of FGF15/19 in the adult is to re-
gulate bile acid homeostasis. Bile acids are amphipathic
molecules that are released post-prandially from the gall-
bladder into the small intestine, where they play an es-
sential role in the solubilization of dietary lipids (Russell
2003). After traversing the intestine, ;95% of bile acids
are reabsorbed in the ileum and returned to the liver and
gallbladder via the portal vein. Because of their intrinsic
toxicity, intracellular levels of bile acids must be tightly
regulated, which is accomplished by the transcriptional
regulation of proteins involved in bile acid biosynthesis,
transport, and metabolism. Chief among the transcrip-
tional regulators of bile acid homeostasis is the farnesoid
X receptor (FXR), a member of the nuclear receptor family
of ligand-activated transcription factors that is activated
by the bile acids cholic acid and chenodeoxycholic acid
(Kalaany and Mangelsdorf 2006). Among the genes regu-
lated by FXR in the liver is cholesterol 7a-hydroxylase
(CYP7A1), which encodes the enzyme that catalyzes the
first and rate-limiting step in the classical bile acid
biosynthetic pathway (Russell and Setchell 1992; Chiang
1998). FXR potently represses CYP7A1 and thus bile acid
synthesis through a two-pronged mechanism (Fig. 1). First,
FXR induces hepatic expression of small heterodimer part-
ner (SHP), an orphan nuclear receptor that binds to the
CYP7A1 promoter and represses its transcription (Goodwin
et al. 2000; Lu et al. 2000). Unlike most nuclear receptors,
SHP lacks a DNA-binding domain and binds indirectly to
the CYP7A1 promoter through interactions with two
other orphan nuclear receptors: liver receptor homolog-1
(LRH-1) and hepatocyte nuclear factor 4a (HNF4a)
(Goodwin et al. 2000; Lu et al. 2000; De Fabiani et al.
2001). The importance of the FXR–SHP pathway in bile
acid homeostasis has been demonstrated in FXR-KO and
SHP-KO mice, both of which have increased Cyp7a1 ex-
pression and a corresponding increase in bile acid pool size
(Kerr et al. 2002; Wang et al. 2002; Kok et al. 2003).
FGF15/19 is part of a second, interrelated mechanism
through which bile acids feed back to repress their own
synthesis (Fig. 1). It has been known for more than two
decades that intestinal administration of bile acids sup-
presses CYP7A1, suggesting that the intestine produces
a secreted factor that acts on the liver to repress bile acid
synthesis (Pandak et al. 1991; Nagano et al. 2004). FGF19
was first implicated as this factor when it was shown that
FXR agonists induced FGF19 in cultured human hepato-
cytes and, further, that FGF19 repressed CYP7A1 expres-
sion in both isolated hepatocytes and mice (Holt et al.
2003). Subsequent studies showed that FXR-mediated re-
pression of Cyp7a1 was lost in FGF15-KO mice, demon-
strating the physiological importance of this pathway
(Inagaki et al. 2005). While the initial studies suggested
that FGF15/19 might be part of an autocrine pathway in
liver, more recent studies in mice showed that FGF15/19
is not normally made in hepatocytes, but is instead ex-
pressed in ileal enterocytes, where it is induced by bile
acids acting on FXR (Inagaki et al. 2005). Consistent with
these findings, FXR-mediated repression of Cyp7a1 re-
(Kim et al. 2007a). In humans, circulating FGF19 concen-
trations increase in response to oral administration of bile
acids and decrease in response to treatment with bile acid
sequestrants, demonstrating that the regulation of FGF15/
19 is conserved (Lundasen et al. 2006; Brufau et al. 2010).
Thus, FGF15/19 signals from the intestine to the liver to
regulate bile acid homeostasis.
FGF15/19 represses CYP7A1 in the liver by binding to
the FGFR4/b-Klotho receptor complex. As was observed
in FGF15-KO mice, FGFR4-KO and b-Klotho-KO mice
have increased Cyp7a1 expression and bile acid synthe-
sis, and administration of exogenous FGF15/19 fails to re-
press Cyp7a1inthese animals(Yu et al. 2000; Inagakiet al.
2005; Ito et al. 2005; Tomiyama et al. 2010). Conversely,
in either wild-type or FGFR4-KO mice decreased Cyp7a1
expression and bile acid pool size (Yu et al. 2005). Impor-
tantly, FGF15/19-mediated repression of Cyp7a1 is lost in
SHP-KO mice (Inagaki et al. 2005), demonstrating that the
induced in the small intestine by bile acids acting on the
FXR/RXR heterodimer. Secreted FGF15 acts on FGFR/b-Klotho
receptor complexes in the liver to repress CYP7A1 and bile acid
synthesis through a mechanism that requires SHP, to induce
protein synthesis through activation of the ERK1/2–RSK path-
way that activates translation factors S6 and eIF4B, to stimulate
glycogen synthase (GS) activity and glycogen synthesis through
inactivation of glycogen synthase kinase 3 (GSK3), and to
repress gluconeogenesis by blocking the phosphorylation and
activation of CREB, a transcription factor that induces peroxi-
some proliferator-activated receptor g coactivator 1-a (PGC-1a)
and other gluconeogenic genes. FGF15 also acts on the gallblad-
der to increase cAMP levels, which promotes filling of the
gallbladder with bile.
Endocrine actions of FGF15. FGF15 expression is
FGF15/19 and FGF21
GENES & DEVELOPMENT313
FGF15/19 and SHP pathways converge. The mechanistic
basis for this cooperativity is not yet known. One possi-
bility is that FGF15/19 increases the stability of SHP by
preventing its ubiquitination (Miao et al. 2009). However,
since increased basal SHP expression in the liver has only
relatively modest effects on Cyp7a1 expression compared
with FGF19 administration (Boulias et al. 2005; Inagaki
et al. 2005; Potthoff et al. 2011), this is unlikely to
account for the full effect of FGF19 on CYP7A1.
Recent studies indicate that the FGF19–CYP7A1 path-
way has medical relevance in humans. Circulating FGF19
concentrations are high in patients with extrahepatic
cholestasis, a condition in which bile flow from the liver
is impeded (Schaap et al. 2009). Interestingly, FGF19 is
expressed in the liver under these disease conditions,
suggesting the existence of an adaptive response to reign
in bile acid production. Conversely, lowserumFGF19con-
centrations were found in patients with idiopathic bile
acid malabsorption (Walters et al. 2009), a disease associ-
ated with excess bile acid production and chronic diarrhea.
Based on these findings, it was proposed that low FGF19
serum levels, not defective ileal reuptake of bile acids, are
the basis for this disease (Walters et al. 2009). Another
study found a single-nucleotide polymorphism in
b-Klotho, which regulated b-Klotho protein stability
and was associated with colonic transit in diarrhea-
predominant irritable bowel syndrome (Wong et al.
2011). In a mouse model of bile acid malabsorption,
FGF15 administration suppressed Cyp7a1 and normal-
ized the bile acid pool (Jung et al. 2007). These findings
raise the intriguing possibility that FGF15/19 or FXR
agonists may have utility in the treatment of diseases
associated with excess bile acids.
In addition to its effects on bile acid synthesis, FGF15/
19 also regulates gallbladder filling (Fig. 1). FGF15-KO
mice have a virtually empty gallbladder even in the fasted
state, when the gallbladder is normally full (Choi et al.
2006). Likewise, FGFR4-KO and b-Klotho-KO mice have
small gallbladders (Yu et al. 2000; Ito et al. 2005). Injection
of recombinant FGF19 into FGF15-KO mice causes a rapid
filling of the gallbladder without stimulating bile flow.
This effect is mediated in part via relaxation of the gall-
bladder smooth muscle (Choi et al. 2006). We conclude
that FGF15/19 plays an overarching role in regulating bile
acid homeostasis, including the post-prandial refilling of
the gallbladder. Interestingly, in humans but not mice,
FGF19 is abundantly expressed in the gallbladder, where
it is secreted into the bile, not the blood (Zweers et al.
2011). The physiological consequences of this exocrine
secretion of FGF19 remain to be determined.
FGF15/19 in energy homeostasis
A role for FGF19 in controlling energy homeostasis was
first discovered using FGF19 transgenic mice. Mice with
constitutively elevated levels of FGF19 have lower body
weights due to reduced fat content, despite having ele-
vated food intake (Tomlinson et al. 2002). In this study,
reduced adiposity and increased food intake were ex-
plained by elevated energy expenditure resulting from
increased brown adipose tissue (BAT) mass and enhanced
hepatic lipid oxidation. FGF19 transgenic mice were also
protected from diet-induced obesity and had lower serum
glucose, insulin, cholesterol, and triglyceride levels. Ad-
ministration of recombinant FGF19 to mice fed a high-fat
diet recapitulated most of these metabolic effects (Fu et al.
2004). To date, the molecular basis of these changes has
not been elucidated, and this remains an active area of
Consistent with the effects of FGF15/19 on metabo-
lism, FGFR4-KO mice show characteristics of metabolic
syndrome, including dyslipidemia, hypercholesterolemia,
increased adiposity, and glucose intolerance (Huang et al.
2007). Paradoxically, however, obese FGFR4-KO mice have
reduced hepatic triglyceride and cholesterol levels due to
increased hepatic fatty acid oxidation and hepatic tri-
glyceride secretion (Huang et al. 2007). Interestingly, re-
expression of a constitutively active form of FGFR4 in
the liver of FGFR4-KO mice decreased plasma lipid and
cholesterol levels but failed to improve the glucose toler-
ance and insulin sensitivity that is seen with FGF19 treat-
to FGFR4-KO mice on a high-fat diet improved glucose
homeostasis (Wu et al. 2011). Thus, FGF19 requires
FGFR4 in the liver to improve dyslipidema and hyper-
cholesterolemia but not hyperglycemia and insulin re-
How does FGF15/19 impact carbohydrate metabolism?
While FGF19 acts preferentially through FGFR4(Xie et al.
1999; Kurosu et al. 2007), it also binds and activates
FGFR1c, which is abundantly expressed in white adipose
tissue (WAT) but not in hepatocytes (Kurosu et al. 2007).
Administration of FGF19 to isolated adipocytes increases
FGF signaling and glucose uptake in a b-Klotho-depen-
dent manner, and FGF19 administration induces ERK1/2
signaling in murine WAT (Kurosu et al. 2007; Wu et al.
2009). In addition toWAT, FGF19 may actonother tissues.
creased the metabolic rate, suggesting that FGF19 can act
directly on the CNS (Fu et al. 2004). Thus, the pharmaco-
logical effects of FGF19 on metabolism may involve
signaling through multiple FGFRs in multiple tissues.
Two recent studies demonstrated physiological roles
for FGF15/19 in regulating glucose homeostasis. Kir et al.
(2011) showed that FGF15-KO mice are glucose-intoler-
ant and store 50% less hepatic glycogen than wild-type
mice. Consistent with this finding, pharmacological ad-
ministration of FGF15/19 stimulated hepatic glycogen
synthesis (Fig. 1). FGF19 increased hepatic glycogen syn-
thase activity by inducing the phosphorylation and in-
activation of glycogen synthase kinase 3a and 3b (Kir et al.
2011). Administration of FGF19 to mice devoid of insulin
restored hepatic glycogen concentrations to normal, dem-
onstrating the insulin-independent effects of this endo-
crine pathway. These findings may explain why IRS1/
IRS2-KO mice, which lack insulin signaling in the liver,
are still able to store hepatic glycogen after a meal (Dong
et al. 2006). In addition to glycogen synthesis, FGF19 also
activated components of the protein translation machinery
and increased hepatic protein synthesis in vivo (Kir et al.
Potthoff et al.
314GENES & DEVELOPMENT
2011). Mechanistically, FGF19 uses a RAS–ERK–p90RSK
pathway to induce phosphorylation of ribosomal protein
S6 and eukaryotic initiation factors eIF4B and eIF4E.
In addition to stimulating glycogen synthesis and pro-
tein synthesis in the liver, FGF15/19 also represses glu-
coneogenesis (Fig. 1; Potthoff et al. 2011). Overexpression
of FGF15 in lean mice suppressed hepatic gluconeogen-
esis without affecting insulin sensitivity. The physiologi-
cal importance of FGF15 was demonstrated using FGF15-
KO and FGFR4-KO mice, which were hyperglycemic and
had elevated gluconeogenesis in the fed state (Potthoff
et al. 2011). FGF15/19 represses gluconeogenesis by inhib-
iting the activity of the transcription factor CREB, a key
regulator of peroxisome proliferator-activated receptor g
coactivator-1a (Pgc-1a) and other gluconeogenic genes.
The overlap in the effects of FGF15/19 and insulin on
hepatic metabolism is striking: Both stimulate hepatic
glycogen and protein synthesis and repress gluconeogen-
esis. However, there are important differences. First, un-
like insulin, FGF15/19 does not stimulate lipogenesis,
as an anti-diabetic therapy. Second, whereas insulin acts
through the insulin receptor–PI3K–Akt pathway, FGF15/
19 mediates its effects through the FGFR/b–Klotho–ERK–
RSK pathway. Finally, there are important temporal dif-
ferences. Insulin is released within minutes of a meal, and
in rodent experiments, serum insulin concentrations and
downstream hepatic Akt phosphorylation peak ;15 min
after a high-carbohydrate/high-fat meal. In contrast, Fgf15
mRNA levels in ileum and downstream ERK1/2 phos-
phorylation in the liver peak ;1 h after feeding (Potthoff
et al. 2011).Likewise, inhumans, FGF19 serum levels peak
;2 h after a meal (Lundasen et al. 2006), and, accordingly,
circulating FGF19 levels in humans negatively corre-
late with fasting glucose levels and metabolic syndrome
(Stejskal et al. 2008; Reiche et al. 2010; Mraz et al. 2011).
Thus, FGF15/19 acts after insulin in the transition from
the fed to the fasted state. Taken together, these studies es-
tablish a post-prandial hormonal program in which insulin
and FGF15/19 coordinately govern nutrient metabolism.
FGF15/19 in cancer
Although the studies discussed above point to a novel
therapeutic use for FGF19 in treating diabetes, an im-
portant caveat is that chronic administration of FGF19
stimulates proliferation. FGF19 transgenic mice develop
hepatocellular carcinomas (HCCs) and liver dysplasia by
10–12 mo of age (Nicholes et al. 2002), and an FGF19-
neutralizing antibody inhibited tumor formation in this
model (Desnoyers et al. 2008). Recently, FGF19 was
shown to be amplified and overexpressed in human HCCs.
In mouse xenograft studies, a neutralizing antibody to
FGF19 blocked the growth of a human HCC cell line
harboring the amplified FGF19 gene (Sawey et al. 2011).
As with the effects of FGF15/19 on metabolism, there
is controversy as to whether its proliferative effects are
mediated through FGFR4. Although one study showed
that FGFR4 is required for FGF19-stimulated growth (Wu
et al. 2010b), deletion of FGFR4 accelerates HCC pro-
gression in a carcinogen-initiated mouse model of tumor-
igenesis (Huang et al. 2009). A possible explanation for
these seemingly contradictory findings is that the FGFR4–
FGF19 pathway has both pro- and anti-carcinogenic ac-
tions. For example, while on the one hand FGF19 induces
b-catenin and cell proliferation (Nicholes et al. 2002;
Desnoyers et al. 2008; Pai et al. 2008), it also suppresses
the synthesis of bile acids, which are tumor promoters.
Several other mouse KO models that increase bile acid
synthesis, including the FXR-KO and SHP-KO mice, also
spontaneously develop HCCs (Kim et al. 2007b; Yang
et al. 2007; Y Zhang et al. 2008). Thus, FGF19 may alter-
nately suppress or enhance tumorigenesis through differ-
ent mechanisms. There has been keen pharmacological
interest in developing novel FGF19 mimetics that elim-
inate the growth-promoting effects while preserving the
potent metabolic effects of FGF19. To this end, it was
recently shown that replacement of two short regions of
FGF19 eliminated its proliferative effects without affecting
The study of FGF21 exploded with the discovery of its po-
tent insulin-sensitizing actions in rodents (Kharitonenkov
et al. 2005). However, despite this plethora of work, much
of the biology of FGF21 and its mechanism of action re-
main controversial and incompletely understood. Part of
the problem in developing a coherent understanding of
FGF21 has come from trying to compare its systemic phar-
macological effects in obese animals with its tissue-specific
effects that occur under more physiological conditions. In
this next section, we attempt to provide some clarity to
this complex picture by considering the pharmacological
and physiological actions of FGF21 within the context
of the different experimental conditions in which they
have been observed.
Discovery and pharmacological actions
Fgf21 was isolated from a mouse embryo cDNA library
in a screen for new FGF family members and was shown
to be abundantly expressed in the adult mouse liver
(Nishimura et al. 2000). A role for FGF21 in regulating
metabolism was first reported by Kharitonenkov et al.
(2005), who showed that FGF21 induced glucose trans-
porter-1 and promoted glucose uptake in murine 3T3-L1
and human primary adipocytes. In this and subsequent
studies doneingenetic and diet-inducedmodels ofobesity,
it was shown that FGF21 administration decreased hepatic
triglycerides, decreased plasma triglycerides and glucose
levels, and caused weight loss by increasing energy ex-
penditure and reducing fat mass without decreasing food
intake (Kharitonenkov et al. 2005; Coskun et al. 2008;
Xu et al. 2009a). In similar studies performed with diabetic
rhesus monkeys, FGF21 decreased plasma glucose, in-
sulin, and triglyceride concentrations; lowered LDL cho-
lesterol and increased HDL cholesterol levels; and caused
modest but significant weight loss (Kharitonenkov et al.
2007). Overall, FGF21 was shown to have remarkable ben-
eficial effects on several metabolic parameters in obese
rodents and primates.
FGF15/19 and FGF21
GENES & DEVELOPMENT315
Consistent with its effects on glucose and lipid metab-
olism, a prominent feature of the pharmacological studies
with FGF21 is its profound effect on insulin sensitivity.
When administered to insulin-resistant rodents, a single
injection of FGF21 decreases blood glucose concentra-
tions and improves glucose tolerance and insulin sensi-
tivity in both leptin-deficient ob/ob mice and diet-in-
duced obese mice (Xu et al. 2009b). In diet-induced obese
mice, these changes are accompanied by increased whole-
body glucose turnover without a decrease in hepatic glu-
cose production. Treatment of diet-induced obese mice
with FGF21 for longer periods (3–6 wk) reverses hepatic
steatosis, decreases hepatic glucose production, and in-
creases insulin-stimulated glucose uptake in the heart,
adipose tissue, and skeletal muscle (Xu et al. 2009a). Like-
wise, administration of FGF21 to ob/ob mice for 8 d im-
proves hepatic insulin sensitivity and also increases liver
glycogen content (Berglund et al. 2009). However, there
was no effect of FGF21 on insulin-stimulated glucose up-
take in peripheral tissues in ob/ob mice. While the basis for
this difference is not clear, there is agreement that FGF21
improves insulin sensitivity at least in part through effects
on hepatic metabolism.
On which tissues does FGF21 act directly to regulate
metabolism? FGF21 functions through receptors com-
posed of b-Klotho and either FGFR1c, FGFR2c, or FGFR3c
(Ogawa etal. 2007;Kharitonenkovet al. 2008;Suzuki etal.
2008). While these FGFRs are ubiquitously expressed,
b-Klotho is enriched in several metabolically active tis-
sues, including the liver, WAT, and BAT (Ito et al. 2000;
Fon Tacer et al. 2010). Consistent with this profile, FGF21
stimulates ERK1/2 phosphorylation and modulates gene
expression in each of these tissues (Kurosu et al. 2007;
Fisher et al. 2010). While relatively little is known about
how FGF21 regulates transcription, it reduces levels of the
lipogenic transcription factor sterol regulatory element-
binding protein-1 in the liver (Badman et al. 2009b; Xu
et al. 2009a) and induces expression of the metabolic
coactivator protein PGC-1a in the liver and WAT (Badman
et al. 2009b; Potthoff et al. 2009; Chau et al. 2010; Fisher
et al. 2011). b-Klotho is also expressed in both the en-
docrine and exocrine pancreas (Johnson et al. 2009; J Repa,
pers. comm.). In rat pancreatic islets, FGF21 treatment
stimulates ERK1/2 and Akt signaling and increases insulin
mRNA and protein levels (Wente et al. 2006). Accordingly,
FGF21 treatment increases islet number and insulin stain-
ing in db/db mice, suggesting that preservation of b-cell
function contributes to the beneficial glycemic actions of
FGF21 (Wente et al. 2006). Finally, b-Klotho is expressed in
the hypothalamus (Coskun et al. 2008),although its precise
localization in this tissue has yet to be reported. FGF21
appearsable to cross the blood–brain barrier (Hsuchou et al.
2007), and direct intracerebroventricular infusion of FGF21
into the brains of diet-induced obese rats increases food
intake and energy expenditure and increases insulin sen-
sitivity due to increased insulin-induced suppression of
both hepatic glucose production and gluconeogenic gene
expression (Sarruf et al. 2010). In a study in which FGF21
was administered for 2 wk by injection, FGF21 increased
expression of the orexigenic hormone neuropeptide Y
(NPY) and decreased expression of the anorexigenic
hormone pro-opiomelanocortin in the hypothalamus
(Coskun et al. 2008). Thus, the pharmacological effects
of FGF21 are likely to be a consequence of it acting both
centrally and peripherally. While one study reported that
FGF21 can function in the absence of b-Klotho to induce
an immediate early transcription factor (Tomiyama et al.
2010), no additional parameters were measured in these
experiments, and it remains to be determined whether
FGF21 has b-Klotho-independent actions.
Physiological actions of FGF21
In contrast to the insulin-sensitizing, pharmacological
actions of FGF21 that are observed in obese animals, the
physiological actions of FGF21 occur in lean animals. In
addition, whereas the pharmacological effects include
the systemic action of FGF21 in multiple organ systems
and tissues (e.g., liver, pancreas, adipose, and CNS), the
physiological actions are likely to occur at lower hor-
mone concentrations and in a more restricted set of
tissues. Important clues as to the physiology of FGF21
have come initially from studying its regulation. FGF21
expression is induced in various tissues in response to
fasting, feeding, and cold. Summaries of the role of FGF21
in these responses follow.
FGF21 in fasting and starvation
showed that FGF21 is strongly induced in the mouse liver
by fasting $12 h (Badman et al. 2007; Inagaki et al. 2007;
Lundasen et al. 2007). Optimal induction of FGF21 by
fasting requires the glucagon receptor (Berglund et al.
2010), which is consistent with FGF21 acting subsequent
to glucagon in the temporal cascade of hormones that
regulate the fasting response. There is also evidence that
FGF21 feeds back to suppress glucagon concentrations
(Kharitonenkov et al. 2005, 2007; Berglund et al. 2009).
Fasting-mediated induction of FGF21 requires the perox-
isomeproliferator-activated receptora (PPARa),anuclear
receptor activated by fatty acids and the fibrate class of
hypolipidemic drugs (Badman et al. 2007; Inagaki et al.
2007; Lundasen et al. 2007). PPARa binds directly to the
Fgf21 gene promoter to induce its transcription (Inagaki
et al. 2007). PPARa plays a crucial role in the adaptive
starvation response: PPARa-KO mice are unable to ade-
quately catabolize fatty acids in the liver and, as a conse-
quence, become steatotic, hypoketonemic, hypoglycemic,
and hypothermic during fasts lasting $24 h (Kersten et al.
1999; Leone et al. 1999; Hashimoto et al. 2000). This
hypoketonemia and hepatic steatosis can be partially
reversed by administration of exogenous FGF21 to the
PPARa-KO mice (Inagaki et al. 2007). FGF21 is also
strongly induced in the mouse liver by a high-fat, low-
carbohydrate ‘‘ketogenic’’ diet (Badman et al. 2007) and by
suckling in mouse neonates (Hondares et al. 2010), con-
ditions that mimic starvation in forcing the body to burn
fatty acids rather than carbohydrates. FGF21 has effects
in lean mice on metabolism, growth, and the phenome-
non of torpor that are all consistent with an important
role for FGF21 in coordinating the adaptive starvation
In 2007, three groups
Potthoff et al.
316 GENES & DEVELOPMENT
response. These effects are summarized in Figure 2 and
are discussed below.
have increased hepatic tricarboxylic acid cycle flux,
gluconeogenesis, fatty acid oxidation, and ketogenesis
(Potthoff et al. 2009). FGF21 induces hepatic expression of
the transcriptional coactivator protein PGC-1a, which
stimulates transcription of genes involved in each of
these metabolic pathways. However, the importance of
PGC-1a induction for FGF21 action remains in question
(Potthoff et al. 2009; Fisher et al. 2011). While the met-
abolic actions of FGF21 are similar to those of glucagon,
FGF21 does not increase glycogenolysis (Potthoff et al.
2009), which is consistent with it being induced 12–24 h
into a fast, when glycogen reserves are already depleted.
Acute knockdown of FGF21 in the livers of mice fed
a ketogenic diet causes hepatic steatosis (Badman et al.
2007), demonstrating that FGF21 is required for the
efficient catabolism of fatty acids. Like PPARa-KO mice,
FGF21-KO mice become hypoglycemic during a 24-h fast,
although the effect is more modest (Potthoff et al. 2009).
These data reveal an important role for FGF21 in regu-
lating glucose production and fatty acid catabolism dur-
In the fed state, FGF21 transgenic mice
(GH) concentrations increase to stimulate lipolysis. How-
ever, the anabolic actions of GH, including the induction
During starvation, circulating growth hormone
of its downstream effector, insulin-like growth factor 1
(IGF-1), are lost in starving animals (Thissen et al. 1994).
This phenomenon of dissociating the catabolic from the
anabolic effects of GH is referred to as ‘‘growth hormone
resistance.’’ A remarkable phenotype of FGF21 transgenic
mice is their diminutive size: FGF21 transgenic mice
weigh substantially less than wild-type mice, while re-
taining their appropriate body proportions (Inagaki et al.
2008). Growth retardation is not due to a decrease in GH
concentrations. Rather, basal GH concentrations are mod-
estly increased. Notably, circulating IGF-1 concentrations
are reduced in FGF21 transgenic mice,as are hepatic levels
of the active, phosphorylated form of the transcription
factor STAT5, a major regulator of IGF-1 transcription
(Inagaki et al. 2008). These studies reveal a role for FGF21
in inducing growth hormone resistance as part of the
adaptive starvation response.
which body temperature and physical activity are re-
duced to conserve energy. Depending on the species,
torpor can reduce energy utilization by as much as 90%
(Geiser 2004). A possible link between FGF21 and torpor
was first suggested by the induction of pancreatic lipases
in the livers of FGF21 transgenic mice, a phenomenon
previously observed in torpid mice (Zhang et al. 2006).
This extrapancreatic induction of lipases may provide
a means for the continuous hydrolysis of fatty acids under
conditions of reduced body temperature (Squire et al.
2003). Under fed conditions, FGF21 transgenic mice do
not have reductions in body temperature or activity.
However, during a 24-h fast, FGF21 transgenic mice
exhibit an ;10°C drop in body temperature, accompanied
by a marked decrease in physical activity (Inagaki et al.
2007). Importantly, FGF21 is not sufficient to cause
torpor. Rather, its overexpression sensitizes lean mice
to starvation-induced torpor. This effect is not a function
of reduced adiposity, since wild-type and FGF21 trans-
genic mice have comparable amounts of adipose tissue
(Inagaki et al. 2008). Studies with FGF21-KO mice
showed that FGF21 is not required for hypothermia or
reduced physical activity during a 24-h fast (Oishi et al.
2010). However, ketogenic diet-induced hypothermia
was reduced in FGF21-KO mice, suggesting that FGF21
may be important in controlling torpor under conditions
of longer-term starvation.
How might FGF21 affect torpor? One possibility is via
regulation of hypothalamic NPY, which regulates fasting-
induced torpor. FGF21 administration increases NPY
mRNA levels in the hypothalamus (Coskun et al. 2008).
Similarly, treatment of mice with a fibrate PPAR agonist
induces hypothermia, accompanied by increased NPY
expression in the hypothalamus, and an NPY-Y1 receptor
antagonist prevents this fibrate-mediated hypothermia
(Chikahisa et al. 2008). However, neither PPARa nor
FGF21 is essential for fasting-mediated induction of
NPY (Oishi et al. 2010). These data suggest that there is
redundancy in the regulation of NPY and that the effects
of FGF21 on body temperature and physical activity are
likely to depend on the metabolic status of the animals.
Torpor is a starvation-induced phenomenon in
FGF21. (Left panel) In response to fasting or fibrate drugs, FGF21
expression is induced in the liver by the PPARa/RXR hetero-
dimer. Secreted FGF21 acts as an endocrine hormone to induce
ketogenesis, gluconeogenesis, and torpor and to inhibit somatic
growth. (Middle panel) In response to feeding or thiazolidine-
dione drugs (TZDs), FGF21 expression is induced by the PPARg/
RXR heterodimer in WAT, where FGF21 acts through an
autocrine mechanism to stimulate PPARg activity. (Right panel)
Pharmacological administration of recombinant FGF21 (rFGF21)
affects multiple tissues and has beneficial effects in metabolic
Endocrine, autocrine, and pharmacological actions of
FGF15/19 and FGF21
GENES & DEVELOPMENT 317
FGF21 in cold adaptation
BAT from FGF21 transgenic mice first suggested that
FGF21 may regulate thermogenesis (Kharitonenkov et al.
2005). Two groups subsequently showed that FGF21 is
induced by cold in BAT (Chartoumpekis et al. 2011;
Hondares et al. 2011), although it is unclear whether
BAT-derived FGF21 acts hormonally or just locally in
BAT itself. Injection of FGF21 into mice stimulated the
expression of thermogenic genes such as uncoupling
protein-1 and deiodinase-2 in BAT and uncoupling pro-
tein-1 in WAT (Coskun et al. 2008; Hondares et al. 2010).
Consistent with this activation of BATand ‘‘browning’’ of
WAT, FGF21 administration causes weight loss in obese
rodents and monkeys, with more striking weight loss in
rodents, whichhave moreBAT (Kharitonenkovetal.2005,
2007; Coskun et al. 2008; Xu et al. 2009a). An interesting
conundrum is how FGF21 contributes to both decreases
(i.e., torpor) and increases in body temperature. As sug-
gested above, the response elicited by FGF21 is likely
a function of both the physiological context (e.g., cold or
starvation) and the tissues that are exposed to FGF21
under these conditions. Interestingly, catecholamines
show the same dichotomy in that they are required for
both torpor and thermogenesis (Swoap and Weinshenker
Morphologic alterations in
FGF21 in feeding
duced in the liver by high-carbohydrate diets (Ma et al.
2006; Uebanso et al. 2011) and in WAT by fasting–
refeeding regimens (Oishi et al. 2011; Dutchak et al.
2012). These responses in the liver and WAT are likely
mediated by carbohydrate response element-binding pro-
tein and PPARg, respectively (Ma et al. 2006; Muise et al.
2008; Wang et al. 2008; Iizuka et al. 2009). Regarding
PPARg, we recently showed that the full insulin-
sensitizing effects of the thiazolidinedione drug (TZD)
rosiglitazone, a potent PPARg agonist, require FGF21
(Dutchak et al. 2012). Importantly, diet-induced obese
FGF21-KO mice are refractory to both the beneficial,
insulin-sensitizing effects of TZDs and TZD side effects
such as weight gain and fluid retention. FGF21 stimulates
PPARg at least in part by preventing its post-translational
sumoylation and inactivation. These results reveal FGF21
to be part of a feed-forward regulatory pathway that
contributes to the fed-state response in WAT (Fig. 2).
Notably, unlike the fasting response that elicits FGF21
release from the liver into circulation, feeding and phar-
macological induction of FGF21 in WAT do not cause
a corresponding increase in circulating levels of FGF21
protein (Dutchak et al. 2012). Thus, FGF21 acts in an
autocrine or paracrine fashion in WAT, much like canon-
ical FGFs. In this regard, basal expression of FGF21 is high
in the exocrine pancreas under nonfasted conditions
when circulating FGF21 is low (Fon Tacer et al. 2010).
Thus, the release of FGF21 into the blood by tissues may
be the exception rather than the rule.
We suggest two possibilities as to why a hormone that
elicits diverse aspects of the starvation response is also
induced in WAT by feeding. First, FGF21 may regulate the
efficient capture of nutrients when they become available
In a surprising twist, FGF21 is in-
following an extended fast. In support of this idea, FGF21
is very strongly induced in WAT under fasting–refeeding
conditions (Oishi et al. 2011). Thus, the actions of FGF21
in WAT may represent an extension of its role in the
adaptive starvation response. A second possibility is that
FGF21 regulates pathways that are important in both the
fed and fasted states. A prominent example of this is
triglyceride synthesis. In the fed state, glucose and fatty
acids are converted to triglyceride in the liver and WAT,
with most triglyceride ultimately stored in WAT. How-
ever, triglyceride synthesis also occurs during fasting,
when only a small fraction of the free fatty acids released
by lipolysis are immediately oxidized. Most free fatty
acids are re-esterified to triglyceride by various tissues,
including WATand the liver (Reshef et al. 2003). This so-
called ‘‘triglyceride/fatty acid cycle’’ may serve as a mech-
anism for controlling the delivery of fatty acids and
glycerol to the liver and other tissues during starvation.
A role for FGF21 in this pathway may explain why
FGF21-KO mice have elevated plasma triglyceride and
free fatty acid concentrations during fasting (Hotta et al.
2009; Potthoff et al. 2009). Moreover, a role for FGF21 in
the triglyceride/fatty acid cycle may also help explain
why FGF21 has alternately been reported to stimulate or
repress lipolysis (Inagaki et al. 2007; Arner et al. 2008; Li
et al. 2009). In experiments in lean, fed FGF21 transgenic
mice and in lean, fed wild-type mice injected with re-
combinant FGF21, circulating free fatty acid concentra-
tions were increased (Inagaki et al. 2007). These studies
further showed that FGF21 treatment increased expres-
sion of hormone-sensitive lipase and adipose triglyceride
lipaseinmurineadipose andinduced glycerolrelease from
differentiated 3T3-L1 adipocytes, a surrogate measure of
lipolysis. While there is agreement that FGF21 increases
lipase expression in adipose (Inagaki et al. 2007; Coskun
et al. 2008), other groups have observed that FGF21
treatment decreases free fatty acid release from 3T3-L1
adipocytes and primary cultures of human adipocytes
(Arner et al. 2008; Li et al. 2009), and FGF21 administra-
tion lowers circulating free fatty acids in obese mice (Xu
et al. 2009a). The pro- and anti-lipolytic effects of FGF21
are reminiscent of those of PPARg agonists (Oakes et al.
2001; Nagashima et al. 2005; Festuccia et al. 2006;
Kershaw et al. 2007). We conclude that the effects of
FGF21 on adipose are complex and likely depend on the
precise physiological or pathophysiological context.
An adverse consequence of the effect of FGF21 on
adipocytes occurs in bone, where pharmacological levels
of FGF21 decrease bone mass (Wei et al. 2012). Con-
versely, FGF21-KO mice have increased bone mass.
FGF21 causes bone loss in part by enhancing the differ-
entiation of bone marrow mesenchymal stem cells into
adipocytes instead of osteoblasts (Wei et al. 2012). Bone
loss is a potential clinical concern as FGF21 is developed
as a drug for treating metabolic disease.
FGF21: mice vs. humans
How is FGF21 regulated in humans? As in mice, circulat-
ing FGF21 levels are induced by fibrates and other PPARa
Potthoff et al.
318GENES & DEVELOPMENT
agonists in humans (Galman et al. 2008; Christodoulides
et al. 2009; Mraz et al. 2011). Circulating FGF21 concen-
trations are also increased in rheumatoid arthritis patients
fasted for 7 d (Galman et al. 2008) and in obese individuals
fed a very low-calorie diet for 3 wk (Mraz et al. 2011).
While these data suggest similarities in the way that
FGF21 is regulated across species, the magnitude of FGF21
induction by PPARa agonists and fasting is modest in
humans compared with mice. Notably, circulating FGF21
levels are not increased in humans by either shorter-term
fasts or ketogenic diets (Galman et al. 2008; Christodoulides
et al. 2009; Dushay et al. 2010) or in subjects with anorexia
nervosa (Dostalova et al. 2008; Fazeli et al. 2010), sug-
gesting that there may be important differences in the
regulation and function of FGF21 between rodents and
It also remains to be determined whether the function
of FGF21 as a fed-state hormone is conserved between
mice and humans. While some groups have detected
FGF21 mRNA in human WAT (X Zhang et al. 2008; Mraz
et al. 2009), others have not (Dushay et al. 2010). In-
terestingly, circulating FGF21 concentrations are in-
creased in human subjects who either are overweight or
have type 2 diabetes, impaired glucose tolerance, or
nonalcoholic fatty liver disease (Chen et al. 2008; Chavez
et al. 2009; Mraz et al. 2009; Cuevas-Ramos et al. 2010;
Dushay et al. 2010; Li et al. 2010, 2011; Matuszek et al.
2010; Yilmaz et al. 2010). It seems likely that this
circulating FGF21 is derived from the liver, perhaps due
to the induction of FGF21 by elevated hepatic lipid and
carbohydrate levels. While the human findings appear to
be at odds with the insulin-sensitizing actions of FGF21
in rodents and monkeys, hepatic FGF21 mRNA levels
and plasma FGF21 concentrations are similarly increased
in diet-induced and genetically obese mice (Muise et al.
2010). Importantly, these mice still respond to pharmaco-
logical doses of FGF21 with improved insulin sensitivity.
One possibility is that obesity and insulin resistance cause
‘‘FGF21 resistance’’ in rodents and humans. While a study
from one group supports this hypothesis (Fisher et al.
2010), another study does not (Hale et al. 2011). The basis
and consequences of increased FGF21 in metabolic disease
remain to be determined.
Insulin and glucagon are the prototypical fed- and fasted-
state hormones. In this context, FGF15/19 and FGF21 can
be considered ‘‘late-acting’’ fed- and fasted-state hor-
mones, respectively, acting on the heels of insulin and
glucagon to regulate metabolism in response to nutri-
tional status (Fig. 3). While FGF15/19 and FGF21 have
effects that overlap with those of insulin and glucagon,
they also have their own distinct actions. For example,
FGF21 sensitizes mice to torpor and suppresses growth,
whereas glucagon does not have these effects. A surpris-
ing twist to the paradigm of FGF21 serving as a starvation
hormone is that it also functions as a fed-state signal in
WAT and the liver. Moreover, while both FGF15/19 and
FGF21 circulate as hormones, there is emerging evidence
that they can also function as autocrine or exocrine
factors. While reconciling all of these findings into
a simple model is difficult, we conclude that FGF15/19
and FGF21 play important roles in coordinating energy
homeostasis under a variety of nutritional conditions.
Both FGF15/19 and FGF21 have remarkable pharma-
cological effects on carbohydrate and lipid metabolism,
particularly in the context of obese animals. Their similar
effects on weight loss and insulin action suggest that they
may act through some of the same tissues and pathways,
but this remains to be determined. The pharmacological
actions of FGF15/19 and FGF21 make them attractive as
future drugs for treating metabolic disease. Indeed, FGF21
is already in clinical trials. However, given their pleio-
tropic effects, additional studies will be required to
address the safety of their long-term use. Obvious con-
cerns include the effects of FGF19 and FGF21 on hepato-
cyte proliferation and bone mass, respectively. For
FGF19, there is already evidence that it may be possible
to engineer safer versions of this hormone for use in
humans (Wu et al. 2010a). In any case, based on their
profound pharmacological and physiological effects on
metabolism, the endocrine FGFs appear poised to have
their own long and storied history.
We thank members of the Mangelsdorf/Kliewer laboratory for
discussion. This work was supported by National Institutes of
Health grants 5R01DK067158 and RL1GM084436 (to D.J.M. and
S.A.K.), the Robert A. Welch Foundation (I-1275 to D.J.M. and
I-1558 to S.A.K.), and the Howard Hughes Medical Institute (to
M.J.P. and D.J.M.).
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