REVIEWS

FGF1 a new weapon to control

type2 diabetes mellitus
Emanuel Gasser1*, ChristopherP.Moutos13*, MichaelDownes1 and RonaldM.Evans1,2
Abstract | A hypercaloric diet combined with a sedentary lifestyle is a major risk factor for the
development of insulin resistance, type2 diabetes mellitus (T2DM) and associated comorbidities.
Standard treatment for T2DM begins with lifestyle modification, and includes oral medications
and insulin therapy to compensate for progressive cell failure. However, current
pharmaceutical options for T2DM are limited in that they do not maintain stable, durable glucose
control without the need for treatment intensification. Furthermore, each medication is
associated with adverse effects, which range from hypoglycaemia to weight gain or bone loss.
Unexpectedly, fibroblast growth factor1 (FGF1) and its low mitogenic variants have emerged as
potentially safe candidates for restoring euglycaemia, without causing overt adverse effects. In
particular, a single peripheral injection of FGF1 can lower glucose to normal levels within hours,
without the risk of hypoglycaemia. Similarly, a single intracerebroventricular injection of FGF1
can induce long-lasting remission of the diabetic phenotype. This Review discusses potential
mechanisms by which centrally administered FGF1 improves central glucose-sensing and
peripheral glucose uptake in a sustained manner. Specifically, we explore the potential crosstalk
between FGF1 and glucose-sensing neuronal circuits, hypothalamic neural stem cells and
synaptic plasticity. Finally, we highlight therapeutic considerations of FGF1 and compare its
metabolic actions with FGF15 (rodents), FGF19 (humans) and FGF21.

1
Gene Expression Laboratory,
Salk Institute for Biological
Studies.
2
Howard Hughes Medical
Institute, Salk Institute for
Biological Studies,
10010North Torrey
Pines Road, LaJolla,
California92037, USA.
3
College of Medicine,
University of Arkansas for
Medical Sciences, 4301West
Markham Street, LittleRock,
Arkansas72205, USA.
*These authors contributed
equally to this work.
Correspondence to R.M.E.
evans@salk.edu
doi:10.1038/nrendo.2017.78
Published online 30 Jun 2017
Type2 diabetes mellitus (T2DM) affects more than
400 million adults worldwide (~9% of the adult popu
lation), a number almost double than that seen in 1980
(REFS1,2). The estimated US$825billion spent globally
each year in direct expenses related to the management
of T2DM will only increase, as the prevalence of the
disease is expected to continue to rise in coming dec
ades3. The current pharmacological paradigm of T2DM
management involves sequential attempts at normo
glycaemia with oral agents, which often culminate in
the need for patients to be placed on insulin to approach
glycaemic control. An increasing number of new drugs
and drug classes have become available to manage the
disease; however, despite initial promise, each option
remains hampered by a combination of adverse effects
and lack of long-term efficacy 4,5. In all, the disease has
largely remained a chronic and progressive condition.
Although stem cell-derived cell replacement could
possibly cure diabetes mellitus, successful metrics have
not been met. With no widely effective treatment, let
alone cure, available and rates of the disease continuing
to rise alongside costs, the toll of T2DM seems to be
unyielding.
In this regard, fibroblast growth factor1 (FGF1)
has emerged as a promising solution to the diabetes
dilemma. Although FGF1 is considered to be a well-
established component of processes such as embryonic
development, wound healing, neurogenesis and angio
genesis, the whole-body Fgf1knockout mouse shows
no deficiency in any of these processes6,7. Indeed, only
in 2014, was FGF1 shown to be a metabolic hormone
crucial for the management of nutrient stress, glycaemic
control and insulin sensitivity 8. Fgf1knockout mice
develop marked hyperglycaemia and insulin resist
ance when challenged with a high-fat diet (HFD). In
ob/ob and db/db mice or diet-induced obesity (DIO)
models, peripheral delivery of a single dose of recom
binant FGF1 (rFGF1) can normalize blood levels of glu
cose within hours, without inducing hypoglycaemia8.
Chronic treatment similarly achieved sustained glucose
lowering, with insulin sensitization observed within
3weeks of initiating therapy 8; no desensitization to the
effects of FGF1 was observed. This work has brought
FGF1 to the forefront as a potential new therapeu
tic approach for insulin sensitization and treatment
ofT2DM.

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Key points
Peripherally or centrally injected fibroblast growth factor 1 (FGF1) confers potent
metabolic benefits in type2 diabetes mellitus (T2DM)
FGF1 produced by ependymal cells of the central nervous system interacts with
tanycytes, astrocytes and glucose-sensing neurons of the hypothalamus to influence
feeding and glycaemic control
Functional recovery of hypothalamic glucose-sensing neurons, as well as neural
regeneration and synaptic plasticity, might be fundamental in achieving sustained
remission of T2DM
FGF1 has the potential to improve glycaemic control, in addition to microvascular
and macrovascular complications, in patients with T2DM
Following on from these original findings, a single
central injection of rFGF1 in mice rendered diabetic
by DIO and low-dose streptozotocin (STZ) was shown
to induce normoglycaemia for up to 18weeks after
injection9. Long-lasting glucose-lowering effects were
also observed after a single central injection of rFGF1
in leptin-deficient ob/ob and leptin receptor-deficient
db/db (on a BKS background) mice, as well as in leptin
receptor-deficient Zucker diabetic fatty rats9. This cen
tral effect was associated with increased hepatic content
of glycogen and was independent of weight loss, reduced
food intake, increased insulin sensitivity or increased
levels of insulin (FIG.1).
Although peripherally injected FGF1 could poten
tially signal centrally, it is less likely to act systemically
than centrally injected FGF1. This raises the challeng
ing question as to the potential mechanism underlying
glycaemic control by the central nervous system (CNS)
and whether this can be exploited for therapeutic use.
In this Review, we discuss the foundation for FGF1 and
the CNS in glycaemic control and how these two might
interact to jointly improve glucose regulation. We then
weigh the metabolic actions of FGF1 against other met
abolically active FGFs. We conclude by noting factors
that must be evaluated in the further development of
FGF-based therapeutics for clinical medicine.
Role of FGF1 in glucose control
Feeding suppression
Initial evidence for a central role of FGF1 in feeding
suppression stemmed from reports of a postprandial
increase in levels of FGF1 and FGF2 in the cerebro
spinal fluid of rats1012. In this context, glucose was
identified as the crucial cue, as both intraperitoneal and
intracerebroventricular (ICV) glucose injections were
sufficient to induce FGF1 release into the cerebrospinal
fluid10. Moreover, ventricular microinfusion of FGF1 and
FGF2 revealed a dose-dependent suppression of feeding
in rats10,12,13.
FGF1 acts in an autocrine and/or paracrine manner,
as binding to heparan sulfate proteoglycans prevents it
from entering the circulation, thus necessitating its local
production14,15. In the brain, ependymal cells lining the
ventricular space constitute the main source of FGF1
production10,1618. Upon glucose stimulation, FGF1 is
secreted by ependymal cells and induces the expres
sion of the early response markers Fos (which encodes
FOS) and Hspb1 (which encodes heat shock protein1)
selectively in glucose-sensing tanycytes lining the ventral
part of the third ventricle and in periventricular hypo
thalamic astrocytes9,10,19,20. The lack of FGF1induced
changes in Fos expression in hypothalamic neurons
points to tanycytes and astrocytes as the primary cel
lular targets of secreted FGF1 in the brain9,19,20. Fos and
Hspb1 induction in astrocytes temporally correlates
with the feeding inhibition elicited by ICV infusion of
FGF1, which is strongest within the initial 26h but sus
tained for 24h11,19,20. FGF receptor1 (FGFR1) is widely
expressed throughout the hypothalamus21,22; internali
zation and retrograde transport of radioactively labelled
125
I-FGF1 and 125I-FGF2 has been observed in distinct
neuronal populations 18h, but not 5h, after ICV admin
istration of FGF1 (REF.23). FGF1 has therefore been pos
tulated to suppress food intake in two phases, an early
response mediated mainly by hypothalamic astrocytes
followed by a neuron-dependent late response19.
Based on the aforementioned findings, the initial neg
ative impact of FGF1 on feeding behaviour is plausibly
mediated by its activation of periventricular astrocytes,
which in turn are known to modulate the activity of ano
rexigenic proopiomelanocortin (POMC) and orexigenic
agouti-related peptide (AgRP) neurons in the arcuate
nucleus (ARC)2427. In addition, the lateral hypothalamic
area (LHA) has been prominently implicated in the
hypophagia-inducing actions of FGF1. Namely, neurons
expressing orexin and melanin-concentrating hormone
within the LHA are considered important players in the
regulation of food intake, arousal and motivated behav
iour 28. In rats, 125I-FGF1 and 125I-FGF2 are internalized
by LHA neurons after ventricular infusion23. Moreover,
bilateral LHA administration of antiserum raised against
either FGF1, FGF2 or their receptor FGFR1, induces
hyperphagia10,29. At the cellular level, FGF1 and FGF2
cause a protein kinaseC (PKC)-dependent inhibition
of a significant fraction of glucose-sensitive LHA neu
rons10. The LHA thus conceivably continues to suppress
food intake, for a limited time window, after the initial
activation of astrocytes by FGF1 has wornoff.
Glucose lowering
In contrast to the feeding effect, the glucose-lowering
effect of FGF1 in diabetic settings was discovered only
in the past few years, and attempts to identify its cellular
and molecular mechanisms are still in the early stages8,9.
In addition, the food suppression component of both
the central and peripheral FGF1 response is transitory,
whereas the glucose-lowering effect is persistent 8,9.
In the periphery, the glucose-lowering effect of
injected or endogenous FGF1 is in part mediated by
the FGF1FGFR1 signalling cascade. Adipose tissue has
been identified as the primary target site of endocrin
ized rFGF1, as AP2Cre driven Fgfr1 ablation negates
its glucose-lowering effects in 8month old DIO mice8.
Notably, endogenous FGF1 is induced during the fed
state in adipose tissue by the nuclear receptor perox
isome proliferator-activated receptor (PPAR), the
same nuclear receptor targeted by insulin-sensitizing
thiazolidinedione (TZD) drugs30. However, in contrast

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Single central injection Chronic peripheral injections

Normoglycaemia sustained Transient feeding suppression Sustained normoglycaemia requires

for weeks or months
No overt change in
insulin sensitivity
Increased hepatic glucose
uptake
Unchanged circulating
levels of insulin
Insulin-dependent glucose-lowering eect
Increased glucose uptake (skeletal muscles)
Increased hepatic synthesis of glycogen
No hypoglycaemic events
repeated injections
Improved insulin sensitivity
Decreased hepatic production
of glucose
Decreased hepatic steatosis
Decreased hepatic inammation
Decreased circulating levels of insulin

Nature Reviews | Endocrinology

Figure 1 | Unique and shared properties of central and peripheral injections of FGF1. The figure depicts the metabolic
properties of fibroblast growth factor1 (FGF1) when administered peripherally or centrally.

to TZDs, rFGF1 therapy does not result in adverse
effects such as weight gain, bone loss or hepatic steato
sis, which creates a very appealing safety profile relative
toTZDs.
Endocrinized rFGF1 has been suggested to limit
hypothalamicpituitaryadrenal (HPA) axis activity
and produce normoglycaemia in rats with STZ-induced
T1DM by decreasing hepatic production of glucose,
hepatic levels of acetyl CoA and lipolysis31. However,
the idea that suppression of the HPA axis is sufficient
to counteract diabetic hyperglycaemia is still contro
versial32,33. Moreover, central injection of rFGF1 in the
lateral or third ventricle of ob/ob mice profoundly lowers
blood levels of glucose, and it does so without affecting
plasma levels of corticosterone9. A concordant explana
tion for both models would be that peripheral and central
injections of rFGF1 achieve similar effects through differ
ent paths8,9. Thus, peripheral action would be initiated by
an FGFR1 signalling cascade in fat, whereas central FGF1
would act through an astrocyteglialneuronal circuit.
A second parallel between peripheral and central
FGF1 action is that each of them seems to rely on intact
insulin signalling, as shown by a lack of efficacy in DIO
mice treated with the insulin receptor antagonist S961
or in high-dose STZ-treated mice with cell ablation9.
In addition, both peripheral and central injections sus
tain glucose lowering without causing hypoglycaemia8,9.
Nonetheless, and despite these parallels, central and
peripheral mechanisms reflect significant differences.
A single peripheral injection of FGF1 in diabetic rodents
triggers acute glucose lowering (within hours) and mul
tiple doses promote insulin sensitization in 3weeks8. By
contrast, a single ICV injection of FGF1 lowers glucose
in about a week and sustains this effect beyond 16weeks,
without insulin sensitization9.
Notably, whereas both FGF1 and FGF2 have been
linked to the central regulation of food intake, only
FGF1 displays glucose-lowering effects after periph
eral injection in ob/ob mice8. This finding is however in
contrast to a more recent (2016) metabolomics study, in
which intravenous injection of FGF2 into STZ-induced
diabetic rats lowered blood levels of glucose34. In addi
tion, to our knowledge, data describing the effects of
central injection of FGF2 in diabetic animals are not
currently available. Notwithstanding this caveat, devi
ating functional repertoires of FGF1 and FGF2, despite
overlapping receptor specificity, could be explained by
the possibility that distinct intracellular pathways are
engaged following FGF1 and FGF2 binding to their
receptor, evoked by characteristic structural changes in
the intracellular receptor domains35.
The sustained normalization of blood levels of glucose in
diabetic animals after a single ICV injection of FGF1,
in the absence of hypoglycaemic episodes, clearly war
rants further mechanistic investigations as an attractive
alternative to current treatment methods. These results
lead us to postulate the existence of an as-yet-unknown
mechanism by which a single central injection of FGF1
might permanently increase peripheral uptake of glucose
by the liver and skeletal muscle9.
Central FGF1 effects possible mechanisms
Glucose-sensing neurons
The significance of the brain in peripheral glucose
homeostasis was first demonstrated by ClaudeBernard36
in 1855, who showed that destruction of the hypothala
mus in dogs induces hyperglycaemia. Almost 100years
later, John Mayer 37 proposed the existence of specialized
hypothalamic cells that monitor changes in glucose con
centrations and commence a corresponding chemical or
electrical response. Definite evidence for the existence
of these glucose-sensing neurons (GSNs) was later pro
vided by the identification of hypothalamic neurons
that alter their firing activities in response to changes in
extracellular glucose concentrations38,39.
Since then, several specific GSN populations have been
identified, mainly within the hypothalamus and different
brain-stem structures40,41. Depending on whether their

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firing frequency is increased or decreased in response
to rising extracellular levels of glucose, they are termed
glucose-excited (GE) or glucose-inhibited (GI) neu
rons, respectively 42,43. Neurons can either utilize glucose
directly or take it up in the form of lactate, which is
produced by neighbouring astrocytes. During eugly
caemia, brain levels of glucose are believed to be in the
range of 0.72.5mM, reaching a maximum of 4.5mM
during severe plasma hyperglycaemia and dropping to
0.20.3mM during plasma hypoglycaemia44,45. Glucose
sensing in GE neurons occurs in a way that is mechanis
tically similar to that in pancreatic cells46. High extra
cellular levels of glucose cause an increased intracellular
ATP-to-ADP ratio, closure of ATP-sensitive potassium
channels, subsequent depolarization of the plasma mem
brane and finally opening of voltage-sensitive calcium
channels42,47,48. However, additional alternative glucose-
sensing mechanisms have been proposed in GE neurons
such as the transient response (TRP) channels49 or the
dimeric Gprotein-coupled sweet receptor T1R2T1R3
(REF.50). Cellular metabolism dependent and independ
ent mechanisms have been reported for GI neurons. In
GI neurons of the ventromedial nucleus of the hypo
thalamus (VMH), firing activity is negatively regulated
by high levels of glucose that inhibit the AMP-activated
kinase (AMPK), which leads to Cl channel opening and
hyperpolarization51,52, whereas the existence of phar
macological glucose detectors has been proposed for
orexin neurons53.
Within the hypothalamus, GE and GI neurons have
been identified in the ARC, the ventromedial hypo
thalamus, the paraventricular hypothalamus and the
LHA43. Depending on their anatomical and neurochem
ical characteristics, the physiological response of GSNs
is likely to vary, but altered reproduction, food intake
and energy expenditure have so far been shown to be
included in their functional repertoire43. In particular,
ample evidence exists for the role of GI neurons, most
notably in the VMH5457, in the sympathetic counter-
regulatory response to hypoglycaemia, which triggers
the secretion of glucagon and adrenaline from pancre
atic cells and the adrenal medulla, respectively, as well
as hepatic production of glucose58,59.
Of all the GSN populations, only the LHA has so
far been directly mechanistically implicated in FGF1
actions. As eluded to earlier, FGF1 application on LHA
neurons decreased neuronal activity in 66% of GSNs
and only in 16% of non-GSNs10. At the same time, none
of the tested VMH neurons responded to FGF1. Within
the LHA, orexin neurons are inhibited, whereas neu
rons expressing melanin-concentrating hormone are
excited by physiological changes in glucose60,61, which
suggests that orexin neurons are the likely targets of
FGF1 actions. Of note, reciprocal synaptic connec
tions exist between orexin neurons and neurons in
the ARC, and the orexin receptors OX1R and OX2R
are widely expressed in neurons of the ARC, VMH,
paraventricular hypothalamus and dorsomedial hypo
thalamus (DMH)62,63. In particular, orexin neurons have
been shown to control, at least in part via the VMH,
the sympathetic output to the liver and skeletal muscles,
which modulates glucose production and uptake,
respectively 64,65. However, the persistent nature of the
glucose-lowering effect, long after cellular signalling
induced by exogenous FGF1 has abated, clearly sug
gests that additional mechanisms apart from the mere
modulation of the activity of existing neuronal networks
are atwork.
Tanycytes neurogenesis
Within the hypothalamus, tanycytes populate the floor
and ventrolateral aspect of the third ventricle, which
places them in immediate proximity to the median
eminence, ARC, VMH and DMH66,67. Tanycytes pos
sess a long process that projects into the parenchyma,
allowing them to come into close contact with neurons
of the hypothalamic nuclei, thus potentially regulat
ing neuroendocrine output and energy homeostasis68.
Tanycytes are able to sense altering plasma levels of glu
cose and respond to focally applied glucose by changes
in intracellular Ca2+ signalling 69,70. Importantly, tany
cytes constitute a hypothalamic pool of neurologic pro
genitor cells in the adult nervous system66,7173, which
holds particular relevance when considering the mecha
nistic ramifications of the long-lasting glucose-lowering
effect of FGF1. Lineage-tracing experiments have
revealed that the neuronal progeny of tanycytes pop
ulates mainly the ARC, but also the VMH, DMH and
LHA71,72. Lineage-traced tanycytes have also been shown
to give rise to astrocytes and proliferating progenitor
cells in the hypothalamic parenchyma71,72,74.
Metabolic stress associated with obesity and diabe
tes mellitus compromises the functional integrity of
the hypothalamic circuits that mediate inflammatory
and neurodegenerative events, which ultimately con
tributes to the derailment of energy homeostasis75. In
mice, hypothalamic inflammation is evident within the
first few days of beginning a HFD, and prolonged HFD
exposure leads to a loss of POMC neurons and apopto
sis in mature neurons, which underlines the exceptional
vulnerability of the hypothalamus to overnutrition7678.
The importance of neural regeneration originating
from progenitor cells residing in the periventricular
zone has been demonstrated most dramatically by the
gradual ablation of AgRP neurons, which is compen
sated for by denovo formation of neurons within the
hypothalamic parenchyma79, whereas acute ablation of
AgRP neurons in adult mice causes severe anorexia and
death80,81. Similarly, weight loss induced by injection of
ciliary neurotrophic factor in mice is counteracted by
hypothalamic neurogenesis73. At the other end of the
spectrum, leptin deficiency or DIO have been shown to
disrupt neural stem cell proliferation in adult mice, thus
preventing the adaptive remodelling of the ARC77,82.
Conversely, short-term HFD feeding is reported to pro
mote neurogenesis in tanycytes of the median eminence
at pre-adult ages83, potentially indicating an initial
compensatory attempt.
Analogous to other neural stem cell populations,
tanycyte proliferation is stimulated by insulin-like
growth factor1 (IGF1) and FGF2 (REFS72,84). A similar
role for FGF1 in tanycyte self-renewal could promote

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neurogenesis to repair neural circuits that have deterio Synaptic plasticity

rated as a consequence of dietary insults (FIG.2). Injection
of a relatively small number of enhanced green fluores
cent protein (eGFP)-labelled leptin receptor (LepR)-
positive neurons (isolated from embryonic day13.5
embryos) into the hypothalamus of up to 1week old
LepR-deficient db/db mice was sufficient to cause a
marked reduction in blood levels of glucose that per
sisted for 9weeks and 13weeks after transplantation85.
Mirroring the effect of central injection of FGF1 in ob/ob
mice, rescue of peripheral glucose homeostasis in adult
mice occurred without changes in plasma levels of
insulin85. Tracing the fate of the injected eGFP-labelled
neurons established their synaptic and functional inte
gration into hypothalamic neurocircuits, thereby prov
ing the receptiveness of hypothalamic neuronal circuits
to cell-mediated repair following metabolically inflicted
damage86.
Synaptic plasticity has been alluded to as a potential
mechanism to explain the long-lasting glucose-lowering
effect of FGF1 (REF.9). Such plasticity involves changes
in synaptic activity and connectivity, thereby providing
a mechanism by which neuronal circuits can adapt to
and maintain responsiveness across a wide range of
stimuli87,88. In contrast to the well-established role
of synaptic plasticity in learning and memory formation,
its function in the hypothalamic neuronal circuits that
control feeding behaviour has only recently been dis
covered89,90. The laboratory of TamsHorvth91 was the
first to show that neurons of the ARC alter their synap
tic connections in response to physiological signals of
nutrient availability such as ghrelin and leptin, which
signal food deprivation and satiety, respectively. Later,
the same group reported that this phenomenon is not
an exclusive feature of the ARC. Leptin was found to

a Healthy b Obesity and/or diabetes c Obesity and/or diabetes after FGF1 intervention

Third
ventricle FGF1

Median eminence

Neuron Synapse Reactive astrocyte

Functionally Defective
Tanycyte
impaired neuron synapse

Newly formed
Astrocyte Dividing tanycyte
neuron

Nature Reviews | Endocrinology

Figure 2 | Mechanisms potentially engaged by FGF1 after central
injection. a| This part depicts the hypothalamic circuits in the median
eminence in states of health. b| Nutrient excess and lack of exercise are
major risk factors for the development of the metabolic syndrome,
specifically obesity, diabetes mellitus, hypertension and dyslipidaemia.
Pathological changes in peripheral organs are accompanied by
hypothalamic inflammation and reduced remodelling of hypothalamic
neurocircuits. In pathological conditions such as diabetes mellitus and
obesity, astrocytes undergo a process of hypertrophy and hyperplasia,
commonly termed reactive astrocytosis or astrogliosis. Increasing neuronal
insults, such as inflammatory or excitotoxicity signals contribute to
a dysfunctional neuronal firing state and even neurodegeneration.
Although rare in adult individuals, neurogenesis, originating from tanycytes
in the third ventricular lining or periventricular astrocytes, is believed to
amend some of the inflicted damage. However, aggravating metabolic
conditions reduce the neurogenic potential of hypothalamic
neuroprogenitor cells. Overall, this contributes to decreased central
glucose sensing and peripheral glucose clearance. c| Owing to the limited
data currently available, one can only speculate about the actions of
fibroblast growth factor1 (FGF1) within this network. Potentially, central
FGF1 remedies the debilitated hypothalamic state in diabetes mellitus by
restoring health (or number) of glucose-sensing neurons, (transiently)
inducing neurogenesis, suppressing reactive astrocytes and restoring
synaptic functionality, which ultimately leads to the observed restoration
of normoglycaemia. The lower panel shows the structure of human FGF1
(PDB ID 2HZ9).

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additionally regulate the synaptic organization of orexin
neurons in the LHA92, and ghrelin was shown to modu
late synapse formation in the hippocampus93 and ventral
tegmental area94. Furthermore, hypercaloric challenges
in the form of a HFD were also found to induce synaptic
remodelling in the ARC95,96. Interestingly, deviations in
the synaptic inputs onto satiety-promoting POMC neu
rons might contribute to the difference in susceptibility
of inbred mouse strains toDIO95.
Depending on the energy state of the organism, syn
apses are formed or removed, and the number of den
drites, as well as the amount of excitatory and inhibitory
inputs, can be varied89. Synaptic adaptations are also
accompanied by intracellular plasticity, encompassing,
for example, mitochondrial fission or fusion in neurons
of the ARC and the VMH9799, or uncoupling of mito
chondrial respiration via mitochondrial uncoupling
protein2in ARC neurons100. In AgRP neurons, synaptic
plasticity in the response to ghrelin has been shown to
involve a presynaptic AMPK-dependent positive feed
back mechanism that allows the glutamatergic activa
tion of AgRP neurons to persist for hours after ghrelin
removal and its resetting by leptin administration101.
Astrocytes too have been connected to the modulation
of synaptic plasticity 102, by contacting and stripping
dysfunctional synapses, releasing glial transmitters and
taking up neurotransmitters from the synaptic cleft, thus
representing the main defence against excitotoxicity and
other neuronal insults103,104. The occurrence of reactive
astrogliosis in response to both acute and chronic high-
fat feeding 76,95 could therefore be potentially damaging
to the synaptic plasticity of ARC neurons105. Additional
support for the role of astrocytes in synaptic plasticity
comes from the findings that hypothalamic astrocytes
respond to leptin by changing levels of glutamate and
glucose transporters106.
Despite some initial evidence, if and how FGF1
affects synaptic plasticity to induce remission of diabetes
mellitus have yet to be determined. Some connections
between FGFs and synaptic plasticity, albeit not in the
hypothalamus, have already been suggested by earlier
studies. FGF2 was reported to promote axonal growth
and sprouting after injury 107 and to influence hippo
campal synaptic plasticity 108. FGF1 has been found to
modulate synaptic plasticity of neurons in the cortico
striatopallidal pathway that involves the synergetic
activation of FGFR1 and the Gprotein-coupled 2A
adrenergic receptor 109. Costimulation of both receptors
caused a marked synergistic increase in neurite forma
tion and spine density in striatopallidal neurons, which
involved a rapid and long-lasting phosphorylation of
extracellular signal-regulated kinases1 and 2 (ERK1/2)
mediated by mitogen-activated protein kinase/ERK
kinases1 and 2 (MEK1/2)109.
With regards to the enduring nature of the
FGF1driven normalization of blood levels of glucose in
diabetic animals, the hysteresis effect, which enables sus
tained activation of AgRP neurons even hours after the
initial ghrelin stimulus, is particularly intriguing 101,105.
Whether central injection of FGF1 elicits a similar sig
nal, causing long-lasting changes in synaptic plasticity
of yet-to-be-identified neuronal subpopulations and
triggering the observed metabolic improvements, is an
intriguing possibility. Given their activation by FGF1
(REFS9,19,20) and their effect on neuronal health and
functionality, astrocytes represent one avenue by which
FGF1 could potentially affect neuronal plasticity in the
hypothalamus (FIG.2).
Central insulin signalling
Considering that FGF1mediated glucose lowering
depends on functional insulin signalling, it is impor
tant to note that all potentially involved central mech
anisms outlined earlier are vulnerable to diminishing
insulin signalling. Ablation of insulin receptor signal
ling in neurons of the ARC110,111, the ventral tegmental
area112 or the dorsal vagal complex in the brainstem113
causes either impaired glucose homeostasis or obesity,
whereas deletion of the insulin receptor in steroidogenic
factor1expressing neurons of the VMH protects against
DIO114,115. In 2016, deletion of the insulin receptor in
astrocytes was shown to negatively affect their function
and morphology, causing changes in glucose transport
across the bloodbrain barrier and ultimately impeding
ARC neurons from monitoring and responding to sys
temic changes in levels of glucose25. Moreover, as dis
cussed earlier, DIO and hyperinsulinaemia put a brake
on neurogenesis in the hypothalamus77,82, which could
imply that insulin signalling must not come to a complete
halt in order for a potential neurogenic effect of FGF1
to occur. Finally, the role of central insulin resistance
in neuronal plasticity has become increasingly recog
nized as a potential cause of the development of cogni
tive impairment, which involves synapse deterioration
and neurodegeneration116,117.
Peripheral glucose uptake
Additional studies are required to address how ICV
FGF1 induces increases in peripheral glucose clearance
in the liver and skeletal muscle, without affecting circu
lating levels of insulin, glucose-induced insulin secre
tion, insulin sensitivity or hepatic glucose output. In
general, GSNs are best known for their control of both
sympathetic and parasympathetic branches of the auto
nomic nervous system40. In response to altering levels of
glucose, the range of actions mediated by the parasym
pathetic autonomic nervous system includes the stimu
lation of pancreatic cell proliferation, insulin secretion
and the secretion of glucagon during hypoglycaemia.
Sympathetic activity stimulates glucagon secretion and
inhibits insulin secretion, promotes thermogenesis in
brown adipose tissue, stimulates adrenaline secretion
by the adrenal glands, enhances lipolysis in white adi
pose tissue and regulates hepatic production of glu
cose40,118. However, there are some indications that the
brain has the capacity to lower blood levels of glucose
via both insulin-dependent and insulin-independent
mechanisms119. In rats, electrical stimulation of VMH
neurons or leptin injection into the VMH, but not into
the LHA, has been shown to increase peripheral glucose
uptake, including that in skeletal muscle, independently
of circulating levels of insulin; these effects are abolished

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by blockade of the sympathetic autonomic nervous sys
tem120,121. Furthermore, leptin has been shown to rescue
and restore normoglycaemia in insulin-deficient mice by
reducing hepatic production of glucose while increasing
tissue glucose122,123.
Metabolic improvements, originating from central
injections of FGF1, are also possibly caused by changes
in the gutliverbrain axis119,124. In particular, the hepatic
portal vein has a major role in hepatic and peripheral
glucose disposal125,126. The portal vein is heavily inner
vated by vagal afferents that express nutrient sensors
and relay information to higher brain centres126. Glucose
delivery directly into the portal vein increases net hepatic
glucose uptake by a neural mechanism, as denervation
of the liver or intraportal infusion of adrenergic block
ers and acetylcholine reduces or increases, respectively,
net hepatic glucose uptake in response to portal glucose
delivery 125,127,128.
Nevertheless, FGF1 is likely to engage novel (neu
ral) glucose-regulatory mechanisms or combinations
thereof, as similar findings have so far not been reported.
Likewise, the involvement of a humoral factor cannot be
excluded at thisstage.
Barrier to FGF1 success mitogenicity
Although isolated as an invitro growth factor, wild-type
FGF1 presents the issue of potential invivo mitogenic
ity. However, whole-body knockout of Fgf1 causes no
change in tissue growth, and the only known defects
are adipose inflammation and a severe form of diabe
tes mellitus in response to dietary stress30. In addition,
several transgenic mouse lines constitutively overex
pressing FGF1 do not present with tumours or organ
growth, which suggests invivo safety over long periods
of exposure129131. Gene expression array studies have
found increased levels of FGF1 in breast, prostate and
ovarian cancers, but a contribution beyond correlation
has not been established132134. Perhaps more impor
tantly, targeted structurefunction studies clearly sug
gest that the mitogenic and glucose-lowering potentials
of FGF1 are separable. FGF1induced growth invitro
is predominantly associated with FGFR3 and FGFR4,
whereas glucose-lowering is mediated by FGFR1
(REFS8,135,136). Indeed, FGF1 binding to FGFR3 and
FGFR4 can be greatly diminished by mutations and/or
deletions in FGF1 that leave its glucose-lowering poten
tial fully intact 8. Thus, the potential for a therapeutically
viable, fully non-mitogenic human FGF1 variant seems
to be highly plausible. Such a variant could be useful in
the context of either a peripheral or central therapeutic
injection strategy.
Alternatives to FGF1
As a class, FGF-targeted pharmaceuticals are not com
pletely new prospects. Various members of the FGF
family have been explored to treat conditions beyond
metabolic disorders. Intravenous recombinant human
FGF7 is an FDA-approved treatment for oral mucosi
tis 137, whereas other members of the FGF family
are being developed for the treatment of ischaemia,
cerebrovascular disease and cardiovascular disease136.
In addition, various FGFR modulators are in clinical
trials for cancer treatment 138. Although the high poten
tial benefits of a non-mitogenic FGF1 therapy for the
treatment of diabetes mellitus and its complications are
tantalizing, the actions of FGF1 must still be validated
in clinical trials139,140.
Other FGFs, namely, FGF15 (rodents), FGF19
(humans) and FGF21, are known factors involved in
energy homeostasis. To a certain extent, FGF19 and
FGF21 have shown metabolic benefits upon central
injection (TABLE1). ICV injections of FGF19 in both ob/ob
and DIO rodents yielded insulin-independent glucose
lowering effects through a CNS-mediated mechanism,
with acute improvements occurring within a few hours
of injection141144. ICV injection of FGF21 to DIO rodents
garners metabolic benefits in the form of increased
energy output and insulin sensitivity linked to weight
loss145,146. In each case, the FGF effect either required
multiple injections or did not have duration compara
ble to a one-time central injection of FGF1. In addition,
concern remains regarding the adverse effects of therapy
with FGF19 or FGF21. FGF19 overexpression has been
shown to promote hepatocellular carcinoma147,148, and
systemic administration of FGF21 has not been fully
divested from noticeable bone loss149. However, non-
mitogenic FGF19 variants have been developed, and
acute benefits of FGF21 are currently being explored136.
At this point, whether central adverse effects mirror
these peripheral ones is unclear.
Clinical considerations for FGF1
Therapeutically, an intracranial injection might not be
necessary to achieve a robust central effect. Achieving
normoglycaemia resembling that of central injection
of FGF1 could possibly occur via an intranasal route.
Derivatives of FGF1 given intranasally are able to locally
induce angiogenesis and neuronal survival in rodents,
with penetrance across the bloodbrain barrier greatly
enhanced when attached to defined transporter pro
teins150,151. Migration into the CNS is believed to occur
through a combination of movement along the olfac
tory nerve, nasal mucosa capillaries and through cere
brospinal fluid via the cribriform plate150,152. Intranasal
delivery of large biologic proteins is conceptually advan
tageous; however, this approach has yet to be adopted
in an approved prescription drug. Also, whether a
single nasal injection would be sufficient to confer the
equivalent long-term benefits seen with central injec
tion is unclear. In addition, even if sufficient levels of
FGF1 could be transferred into the CNS, this might or
might not be optimal for key target sites. Developing a
therapeutically effective FGF1 targeted to the CNS by
means other than direct intracranial application would
first require a better understanding of the specific brain
regions mediating the metabolic actions of the peptide.
Nonetheless, the idea of a non-invasive route remains
appealing in that it would greatly improve accessibility,
as self-delivery of doses would be possible.
Controlling blood glucose by either peripheral or
central delivery will go far to alleviate short-term com
plications of diabetes mellitus, such as hypoglycaemic

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Table 1 | Comparison of FGF1 with FGF15 (rodents), FGF19 (humans) and FGF21 in diabetic animal models
FGF1 FGF15 or FGF19 FGF21
General properties 8,136

Receptor specificity All seven isoforms; glucose Primarily FGFR1 and Primarily FGFR1
lowering via FGFR1 FGFR4
Receptor-binding requirements Heparin dependent Klotho coreceptor Klotho coreceptor
dependent dependent
Classification Autocrine and/or paracrine Autocrine and/or Autocrine and/or
endocrine endocrine
Induction prompt (tissue) Fed state (adipose) Fed state (gut) Fasted state (liver)
Central actions9,141143,145
Feeding suppression Transient Transient None*
Glucose-lowering duration Months Hours Hours
Hypoglycaemic events None NA NA
Insulin sensitizer
No No No
Peripheral actions8,144,170173
Feeding suppression Transient None None
Glucose-lowering duration 37days Hours Hours
Hypoglycaemic events None NA NA
Insulin sensitizer Yes No No
FGF1, fibroblast growth factor1; FGFR1, FGF receptor1; NA, not available. *Increased food intake. Defined as increased insulin
sensitivity not secondary to body weight loss (for example, thiazolidinediones). Food consumption increased when normalized to
body weight reduction.

episodes, hyperosmolar hyperglycaemic states, diabetic
ketoacidosis and diabetic comas. Ultimately though, the
success of any intervention to treat or possibly cure dia
betes mellitus will rely on more than regulating levels of
glucose. The value of any solution must also be judged
by its ability to limit chronic complications of diabetes
mellitus, both microvascular (retinopathy, nephropathy
and neuropathy) and macrovascular (cardiovascular
disease). Traditionally, the standard of treatment has
focused heavily on achieving glucose, and in turn HbA1c
targets. Current evidence indicates that microvascular
complications can be greatly limited by reaching des
ignated HbA1c goals. However, the same clear, direct
benefit of consistent glycaemic control in risk reduction
as measured by HbA1c cannot be applied as confidently
to macrovascular concerns153155. It must be noted that,
in either case, increasing evidence points towards large
intra-day fluctuations in glucose, specifically in post
prandial glucose, as a driver of complications, independ
ent of chronic hyperglycaemia. These acute changes are
believed to create periods of exacerbated inflammation,
oxidative stress and off-target glycation. The detriment
of intra-day hyperglycaemia applies even in individuals
with acceptable levels of HbA1c, who might be subject to
multiple peaks and troughs throughout the day despite
apparently sufficient metabolic control156158. Current
antidiabetic options, insulin in particular, frequently
subject patients to these large variations in levels of
glucose. This phenomenon has not been observed in
preclinical FGF1 studies thusfar.
Along with large glycaemic swings, the contribu
tion of T2DM to macrovascular complications can also
be attributed to disruptions in PPAR pathways that
promote inflammation via vascular endothelial cells159,160.
As already discussed, FGF1 works along the PPAR axis.
Hepatically, rFGF1 is able to reduce inflammation; thus,
by extension, rFGF1 could confer similar benefits on
the cardiovascular system161. Furthermore, the ability
of peripherally injected FGF1 to relieve insulin resist
ance8 and normalize levels of insulin in patients with
T2DM would logically be expected to reduce the risk of
stroke162,163, diabetic retinopathy and hypertension164.
Limitations of the current data
The failure of central FGF1 to work in DIO mice raises
a major concern as to whether it would be effective in
patients with T2DM and obesity. Alas, data on peripheral
or central actions of FGF1 in humans or non-human pri
mates are not currently available. It is therefore impor
tant to emphasize that most of the findings discussed
in this Review were obtained from work performed in
rodents; any extrapolation to humans must be done so
critically. Despite the vast amount of knowledge obtained
from animal models, only a finite number of antidia
betic drugs in preclinical development have successfully
advanced to clinical use. To some extent, species-specific
variations in glucose regulation can be blamed for the
limited interspecies translatability. Notable examples
include differences in the major site of peripheral glu
cose disposal, the liver in rodents and skeletal muscle
in humans. Differences also exist in the hepatic glucose
production rate, islet architecture, islet innervation and
glucose sensing by pancreatic cells165,166.
Species differences on a genomic and proteomic level,
as well as deviations in pathway engagement, have been
described with regards to glucose sensing in pancreatic

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cells, which suggests a similar scenario for their central
counterparts165. Furthermore, inbred diabetic mouse or
rat models are often diabetic of monogenetic origin that
is present from birth. These strains acquire rapid onset
of obesity early in life mainly owing to hyperphagia and
decreased energy expenditure, with only moderate vas
cular and inflammatory complications. These models
thus do not fully reflect the multifactorial disease aetio
logy in humans, in which environmental influences
are superimposed on genetic risk factors, and disease
onset is more gradual and confounded by microvascular
and macrovascular defects167,168. This limitation is par
ticularly relevant in the development and treatment of
T2DM. With the jury still out on the actions of FGF1 on
the HPA axis, one must also consider that the adverse
effects of toxic glucose analogues such as STZ (which
are used for the induction of a diabetic pathophysiology
in rodents) are not confined to the pancreas and include
disruption to the HPA axis in their repertoire169.
Conclusions
Clear mechanistic understandings of the endogenous
and pharmacologic actions of FGF1 have yet to be
described. However, the remarkable ability of peripher
ally delivered FGF1 to rapidly restore normal glycaemic
levels in diabetic mouse models and function as an insu
lin sensitizer, combined with the longevity in glucose
control achieved with central delivery, alludes to exciting
opportunities for entirely new therapeutic approaches in
the treatment of T2DM. This enthusiasm will gain cred
ibility with preclinical results in higher-order mammals
and the development of truly non-mitogenic analogues.

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Acknowledgements
E.G. is supported by the Swiss National Science Foundation
(grant P2EZP3_172178). C.P.M. is a Howard Hughes
Medical Institute Medical Research Fellow. R.M.E. is an
Investigator of the Howard Hughes Medical Institute at the
Salk Institute and March of Dimes Chair in Molecular and
Developmental Biology, and is supported by NIH grants
(DK057978, HL088093, HL105278 and ES010337), an
National Cancer Institute (NCI) Cancer Center Support Grant
(CA014195), the Glenn Foundation for Medical Research,
and grants from Steven and Lisa Altman and the Leona M.
and Harry B. Helmsley Charitable Trust (2012PGMED002).
Author contributions
E.G., C.P.M., M.D. and R.M.E. researched data for the article
and wrote the manuscript. All authors contributed to discus-
sion of the content and reviewed and/or edited the manu-
script before submission.
Competing interests statement
M.D. and R.M.E are coinventors of mutated FGF1 proteins
and methods of their use (US Patent No. 8,906,854) and
might be entitled to royalties.
Publishers note
Springer Nature remains neutral with regard to jurisdictional
claims in published maps and institutional affiliations.
Review criteria
PubMed was searched for relevant topics, using the search
terms FGF1, FGF, type2 diabetes, glucose-sensing
neurons, glucose-lowering mechanisms, glucose homeo-
stasis, glucose uptake, glycemic control, neuronal con-
trol, central control, food intake, appetite,
neurogenesis, synaptic plasticity, neuronal plasticity,
tanycytes, hypothalamus, hypothalamic inflammation
and intranasal, and combinations thereof. No publication
time constraints were applied. References cited in this arti-
cle include both original research and reviews by experts in
the field.

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