Cell Metabolism

Previews
Turn Up the Heat: Circulating Serotonin
Tunes Our Internal Heating System
Jochen G. Schneider1,2,* and Joseph H. Nadeau3,*
1Luxembourg Centre for Systems Biomedicine (LCSB), Campus Belval, 7 Avenue des Hauts Fourneaux, L-4362 Esch, Luxembourg,
Luxembourg
2Department of Internal Medicine II, Saarland University Medical Center at Homburg/Saar, Kirrberger Strae 100, D-66424 Homburg,
Germany
3Pacific Northwest Research Institute, 720 Broadway, Seattle, WA 98122, USA
*Correspondence: jg.schneider@outlook.com (J.G.S.), jnadeau@pnri.org (J.H.N.)
http://dx.doi.org/10.1016/j.cmet.2015.01.011

Serotonin acts as neurotransmitter in the brain and as a multifaceted signaling molecule coordinating many
physiological processes in the periphery. In a recent issue of Nature Medicine, Crane et al. (2014) find that
peripheral serotonin controls thermogenesis in adipose tissue by modulating b-adrenergic stimulation of
UCP-1, thereby affecting glucose homeostasis and weight gain.

Serotonin (5-hydroxytryptamine, 5-HT) is

a biogenic amine synthesized in a twostep enzymatic reaction (Berger et al.,
2009): First, enzymes encoded by one
of two tryptophan hydroxylase genes
(Tph1 or Tph2) catalyze the rate-limiting
conversion of tryptophan to 5-hydroxytryptophan (5-HTP), thus allocating the
bioactivity of serotonin into either the
brain (Tph2) or the periphery (Tph1).
Then, 5-HTP undergoes decarboxylation
to serotonin. Serotonin metabolism must
be independently regulated in the brain
and periphery because the blood-brain
barrier partitions bioavailability. The
Tph2-dependent serotoninergic system
acts solely at specific sites in the brain,
which accounts for 2%5% of total
body serotonin (Zhang et al., 2004). In
the brain, serotonin modulates mood,
anxiety, appetite, and potentially cognitive performance. Therapeutic aspects
of serotonin in the CNS have been
explored with mixed results. While serotonin reuptake inhibitors are widely used
to treat depression and anxiety, the pharmacological increase of central serotonin
using fenfluramine to modulate appetite
failed due to adverse cardiovascular
side effects. Tph1 is widely expressed in
the periphery, with the majority (95%
98%) of total body serotonin found in
the gut (Berger et al., 2009). Peripheral
serotonin acts autonomously on many
cells, tissues, and organs, including the
cardiovascular, gastrointestinal, hematopoietic, and immune systems as well as
bone, liver, and placenta (Amireault
et al., 2013). Serotonin functions as a

ligand for any of 15 membrane-bound

mostly G protein-coupled serotonin receptors (5-HTRs) that are involved in
various signal transduction pathways in
both CNS and periphery (Berger et al.,
2009). Thus serotonin coordinates molecular and physiological activities across
diverse signal transduction pathways
in many tissue and organ systems
throughout development and adulthood.
Dissecting pathways and targets that
control the relations between circulating
serotonin and diet-induced obesity has
been a major challenge (Kim et al.,
2011). A new study published in Nature
Medicine provides clarity by identifying
a novel role for serotonin in regulating
thermogenesis in brown adipose tissue
(BAT) with effects on energy balance,
obesity, and related metabolic conditions
(Crane et al., 2014).
Promoting thermogenesis in BAT has
become an attractive target for the treatment of obesity since BAT was recently
discovered in the neck and mediastinum
of humans (Cypess et al., 2009). Thermogenesis in BAT can be activated by cold
exposure or by activating the sympathetic
nervous system, resulting in conversion of
energy resources into heat, instead of
activating ATP synthase to produce ATP.
Disconnecting respiration from oxidative
phosphorylation is mediated by b-adrenergic-dependent expression of uncoupling proteins (UCPs) that allow protons
to leak through the inner mitochondrial
membrane. Three UCP isoforms are
known, one of which is expressed in the
brown and beige adipose tissue (UCP1).

156 Cell Metabolism 21, February 3, 2015 2015 Elsevier Inc.

Facilitating metabolic uncoupling might

control obesity and related conditions
such as insulin resistance.
Crane and colleagues (Crane et al.,
2014) aimed to probe a direct role of peripheral serotonin on obesity and related
conditions. They found that not only did
Tph1-deficient mice have lower circulating serotonin levels, as expected, but
they also showed increased oxygen consumption, elevated interscapular temperature, and enhanced glucose uptake, all
of which point to BAT as the metabolic
mediator for these effects (Stanford
et al., 2013). Isoproterenol, a b-adrenoceptor agonist, increases BAT-dependent
b-adrenergic signaling by modulating
cAMP levels, thereby increasing UCP1
expression. Serotonin, when given at the
same time, blunts this effect, showing
that serotonin reduces sympathetic activation (Crane et al., 2014). When fed a
HFD, Tph1-deficient mice showed
reduced weight gain and adiposity, suppressed glucose intolerance, and insulin
resistance as well as less severe fatty
liver disease compared to controls. The
authors then intraperitoneally treated
HFD-fed wild-type and UCP1-deficient
mice under thermoneutral conditions
for 12 weeks with a small molecule
(LP533401) that inhibits serotonin production. The treatment recapitulated the
improved metabolic effects found in
HFD-fed Tph1-deficient mice, with the
beneficial effects requiring UCP1 activity,
since only treated UCP1-wild-type, but
not UCP1-deficient mice, responded
with reduced weight gain, lower adiposity,

Cell Metabolism

Previews

Adipogenesis
Lipolysis
Thermogenesis

Bile acid turnover

FXR signaling

Glucose import
Glucose metabolism

Peripheral
Serotonin
-cell funcon
Cell proliferaon
Insulin release

Gluconeogenesis
Glucose uptake

Figure 1. Physiological Actions of Peripheral Serotonin on Metabolic Target Organs

Effects on thermogenesis as shown by Crane et al. (2014) are shown in red. Red arrows point to the metabolically active organs that are influenced by peripheral
serotonin action. Physiological functions affected are listed adjacent to the organs.

and improved glucose tolerance when fed

with HFD. However, the identity of the
serotonin receptor(s) and the underlying
signaling mechanism for these serotonininduced effects in BAT remain unknown.
Additionally, both genotypes displayed a
reduced adipose tissue inflammation and
interleukin-6 serum levels under serotonin
inhibition, suggesting thermogenesis-independent effects.
A deeper look reveals several issues
that further complicate the story. Crane
and colleagues (Crane et al., 2014) provide evidence concerning weight gain in
Tph1-deficient mice, though the results
regarding related metabolic traits, such
as glucose metabolism, insulin resistance,
and lipolysis, are not entirely consistent
with published reports. For example, Paulmann et al. showed that Tph1-deficient
mice are diabetic on chow diet and mildly
insulin resistant at young ages (Paulmann
et al., 2009). The authors reported a secretory defect in pancreatic b cells depending
on defective intracellular, receptor-independent serotonylation of GTPases,
while systemic serotonin administration
reduced insulin secretion. Surprisingly,
no effects on circulating lipids were reported here or by Crane and colleagues.

Peripheral serotonin acts cell autonomously by employing different sets of

5HTRs or in a receptor-independent
fashion (Berger et al., 2009, Paulmann
et al., 2009). Tph1 has been shown to be
involved in adipose tissue regulation, and
serotonin may act as ligand for PPARg
(Watanabe et al., 2011). Thus, unwanted
and even off-target effects must be
considered with systemic antagonists.
Genetic deletion of Tph1 in mice may
also differ from its pharmacological inhibition, phenomena that are known from
other molecular targeting studies. In
addition, gut-derived serotonin activates
lipolysis in adipocytes through increased
phosphorylation of hormone-sensitive lipase (HSL) (Sumara et al., 2012), contrary
to the effect reported by Crane and colleagues in beige adipocytes and mainly
caused by circulating gut-derived serotonin. Such differences may depend on the
dose and route of administration as well
as on genetic background (Berger et al.,
2009; Crane et al., 2014; Sumara et al.,
2012). Finally, central serotonin has established effects on body weight, but neither
definitive human data on central effects
nor data on the role of peripheral serotonin
in human obesity have been reported.

Crane and colleagues (Crane et al.,

2014) have elegantly shown the sympathetic signaling-dependent action of serotonin on thermogenesis and lipolysis and
thus have possibly identified a novel intervention for obesity and associated metabolic parameters (Figure 1). However,
manipulating serotonin availability for targeting a specific disease remains challenging given serotonins diverse targets
and functions.
REFERENCES
Amireault, P., Sibon, D., and Cote, F. (2013). ACS
Chem. Neurosci. 4, 6471.
Berger, M., Gray, J.A., and Roth, B.L. (2009). Annu.
Rev. Med. 60, 355366.
Crane, J.D., Palanivel, R., Mottillo, E.P., Bujak,
A.L., Wang, H., Ford, R.J., Collins, A., Blumer,
R.M., Fullerton, M.D., Yabut, J.M., et al.
(2014). Nat. Med. http://dx.doi.org/10.1038/nm.
3766.
Cypess, A.M., Lehman, S., Williams, G., Tal, I.,
Rodman, D., Goldfine, A.B., Kuo, F.C., Palmer,
E.L., Tseng, Y.H., Doria, A., et al. (2009). N. Engl.
J. Med. 360, 15091517.
Kim, H.J., Kim, J.H., Noh, S., Hur, H.J., Sung, M.J.,
Hwang, J.T., Park, J.H., Yang, H.J., Kim, M.S.,
Kwon, D.Y., and Yoon, S.H. (2011). J. Proteome
Res. 10, 722731.

Cell Metabolism 21, February 3, 2015 2015 Elsevier Inc. 157

Cell Metabolism

Previews
Paulmann, N., Grohmann, M., Voigt, J.P., Bert, B.,
Vowinckel, J., Bader, M., Skelin, M., Jevsek, M.,
Fink, H., Rupnik, M., and Walther, D.J. (2009).
PLoS Biol. 7, e1000229.

K.R., Nakano, K., Hirshman, M.F., Tseng, Y.H.,

and Goodyear, L.J. (2013). J. Clin. Invest. 123,
215223.

Stanford, K.I., Middelbeek, R.J., Townsend, K.L.,

An, D., Nygaard, E.B., Hitchcox, K.M., Markan,

Sumara, G., Sumara, O., Kim, J.K., and Karsenty,

G. (2012). Cell Metab. 16, 588600.

158 Cell Metabolism 21, February 3, 2015 2015 Elsevier Inc.

Watanabe, H., Rose, M.T., and Aso, H. (2011).

Curr. Opin. Lipidol. 22, 186191.
Zhang, X., Beaulieu, J.M., Sotnikova, T.D., Gainetdinov, R.R., and Caron, M.G. (2004). Science
305, 217.