Letter

# Tanycytes and hypothalamic FGF21: New players in the metabolic game

Sarah Geller<fnref n="1" />,<fnref n="3" />,* and Luc Pellerin<fnref n="2" />,<fnref n="3" />,<fnref n="4" />,*

The actual obesity and diabetes pand-
demics require new approaches to
stop their progression. Recent findings
converged on the therapeutic potential
of fibroblast growth factor 21 (FGF21) in
these metabolic diseases. FGF21 is a
master regulator of metabolism by
acting not only directly on peripheral
tissues but also through the brain. The
central nervous system seems to be a
target for the beneficial effects of
FGF21 in the treatment of diabetes (in
particular, insulin resistance) as well as
obesity, highlighting the importance of
investigating its central mechanisms of
action. The source of this messenger
and its target cells in the brain are
debated topics that currently raise
great interest in the field of metabolism.
Under physiological conditions, the liver
is the major source of circulating Fgf21.
Fgf21 protein can cross the blood-brain
barrier by simple diffusion<fnref n="1" /> but also
reach part of the brain via fenestrated
vessels in the hypothalamus.<fnref n="2" /> Recently,
Zhou et al. reported in this journal
a central production of neuronal Fgf21
in the thalamus and the retrosplenial
cortex.<fnref n="3" /> This neuronal production of
Fgf21 seems to be involved in the
enhancement of spatial memory but
does not regulate energy homeostasis
or sugar intake. More surprisingly, in
contrast to several recent studies, they
did not detect Fgf21 production in the
hypothalamus using a new transgenic
mouse model. Over the past three
years, several studies from indepen-
dent groups with various experimental
conditions reported *Fgf21* mRNA
expression by the hypothalamus in
mouse,<fnref n="4" />⁻⁷ rat,<fnref n="4" />,⁸,⁹ and pig¹⁰ by using,

among other techniques, PCR and
*in situ* hybridization (such as the
novel RNAscope technology). More-
over, three of these studies described
an *Fgf21* mRNA synthesis by glial
cells including tanycytes,⁶,⁷,⁹ peculiar
ependymal cells of the hypothalamus.
The recent challenge by Zhou et al.<fnref n="3" />
of a specific tanycytic Fgf21 pro-
duction created a controversial issue
on whether the protein detected in ta-
nycytes is produced locally or comes
from the bloodstream. Interestingly,
a parallel study confirmed a mixed
origin of Fgf21 protein detected in tany-
cytes.⁹ This study validated that rat ta-
nycytes synthesize *Fgf21* mRNA but
also demonstrated that they transport
peripheral Fgf21 protein into the hypo-
thalamus. Indeed, hepatic Fgf21 rea-
ches deeper hypothalamic structures
through active transport by tanycytes,
a mechanism shown to be necessary
to observe a beneficial effect on sys-
temic metabolism in animals that un-
derwent delayed weaning and were
exposed to a high-fat diet later in life.⁹
Intriguingly, hepatic and hypothalamic
*Fgf21* mRNA expression seem to be
either similarly or differentially regulated
according to the type of nutrients.
Although a first study showed that fast-
ing and fatty acids (such as palmitate)
stimulate both hepatic and tanycytic
*Fgf21* mRNA expression,⁶ delayed
weaning or protein deficiency induced
an opposite effect on *Fgf21* mRNA
expression from both tissues.⁸,⁹ These
observations confirm a complex regula-
tion of Fgf21 production according to
the tissue and nutritional status. The
mechanisms responsible for these spe-

cific regulations need to be identified
and described. Moreover, the opposite
effects of nutrients on hypothalamic
and hepatic *Fgf21* mRNA expression
raise the question about the existence
of a counter-regulation or compensa-
tion system that must be coordinated
somehow between both structures.
Furthermore, one may wonder, *in fine*,
what is the benefit of parallel tanycytic
*Fgf21* production and active transport
of hepatic *Fgf21* by tanycytes? It is
clear that the physiological functions
of such a glial *Fgf21* production need
to be further explored and more firmly
established, although specific roles in
systemic lipid and glucose homeostasis
have been unraveled in lean rodents.⁶,⁷
Undoubtedly, tanycytes have joined the
*Fgf21* team, but we need more time to
read their game if we want to win
against obesity and diabetes.

REFERENCES

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<figure><img src="image_1.png" /></figure>

<footnote n="1">¹Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland</footnote>

<footnote n="2">²Inserm U1313 IRMETIST, Université de Poitiers et CHU de Poitiers, Poitiers, France</footnote>

<footnote n="3">³These authors contributed equally</footnote>

<footnote n="4">⁴Lead contact</footnote>

<footnote>*Correspondence: sarah.geller@unil.ch (S.G.), luc.pellerin@univ-poitiers.fr (L.P.)</footnote>

<footnote>https://doi.org/10.1016/j.celrep.2022.111954</footnote>
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