Brain Activation in Uremic Anorexia

Abelardo Aguilera, MD, José Antonio Sánchez-Tomero, MD, PhD,

and Rafael Selgas, MD, PhD

This article reviews current knowledge about mechanisms responsible for uremic events, especially those that
involve the central nervous system (CNS). Anorexia is a frequent complication of the uremic syndrome that
contributes to malnutrition in patients on dialysis. Uremic anorexia has been associated with many factors.
Traditionally, anorexia in dialysis patients has been regarded as a sign of uremic toxicity; therefore, 2 hypotheses
have been proposed: the “middle molecule” and “peak concentration” hypotheses; both of these remain unproved.
Recently, our group has proposed the tryptophan-serotonin hypothesis, which is based on a disorder in the amino
acid profile that may be acquired when the patient is in uremic status. It is characterized by low concentrations of
large neutral and branched chain amino acids in the cerebrospinal fluid. This situation permits a high level of
tryptophan transport across the blood– brain barrier and enhances the synthesis of serotonin (the final target
responsible for inhibiting appetite). The role of inflammation in the genesis of anorexia–malnutrition is also
emphasized. In summary, in the CNS, factors associated with uremic anorexia include high levels within the
cerebrospinal fluid of proinflammatory cytokines, leptin, and free tryptophan and serotonin (hyperserotoninergic-
like syndrome), along with deficiency of neural nitric oxide (nNO) and disorders in various receptors such as
melanocortin receptor-4 (MC4-R). Uremic anorexia is a complex complication associated with malnutrition and high
levels of morbidity and mortality. Several uremia-acquired disorders in the CNS such as high cerebrospinal fluid
levels of anorexigen substances and disorders in appetite regulator receptors may explain the lack of appetite.
© 2007 by the National Kidney Foundation, Inc.

A NOREXIA IS A FREQUENT symptom of

uremic syndrome that contributes to mal-
nutrition in patients on dialysis. The clinical rel-
evance of anorexia and malnutrition in patients
on dialysis is related to associated levels of mor-
bidity, mortality, and hospitalization.1,2 Tradi-
tionally, anorexia has been considered a sign of
uremic intoxication; it has been used as a clinical
marker to initiate dialysis or define it as inade-
quate.1 In dialysis patients, appetite regulation is
complicated for the abnormal metabolism and
renal retention of several substances; effects on
the hunger–satiety cycle have been observed.
Frequently, in uremic patients, this equilibrium is
influenced to induce anorexia through the pre-
dominant renal retention of peptides and cyto-
kines.3 However, the exact cause of uremic an-
orexia is unknown. This paper reviews current
Servicio de Nefrologia, Hospitales Universitarios de la Princesa y
la Paz, Madrid, Spain.
Address reprint requests to Abelardo Aguilera, MD, Servicio de
Nefrologia, Hospitales Universitarios de la Princesa, Diego de Leon
62, 28046 Madrid, Spain. E-mail: aguileraa@terra.es
© 2007 by the National Kidney Foundation, Inc.
1051-2276/07/1701-0010$32.00/0
doi:10.1053/j.jrn.2006.10.020
knowledge about the mechanisms responsible for
uremic anorexia, especially disorders involving
the central nervous system (CNS).
Regulation of food intake involves a heteroge-
neous feedback system that requires the participa-
tion of various signals derived from gastrointestinal
tract (GIT), liver, circulating nutrients, fat stores,
and metabolizing cell products, all of which transmit
information to the CNS. Inputs from the peripheral
nervous system, including the vagus nerve and its
gastric receptors, are also important. Signals are
integrated into the CNS, thereby inducing hunger
or satiety. Within the CNS, the hypothalamus con-
tains the feeding center (lateral hypothalamus) with
dopaminergic receptors, along with the satiety cen-
ter (ventromedial hypothalamus) with serotoniner-
gic and adrenergic neurotransmitters.4 Two impor-
tant pathways are included in the hypothalamus:
melanocortin receptor-4 (MC4-R) and pro-
opimelanocortin (POMC) stimulation.5 Under
normal conditions, the activity of MC4-R is in-
creased in 2 ways: through suppression of orexigen
hormones such as neuropeptide Y (NPY) and ag-
outi-relative protein–like (AGRP) activation of
POMC-expressing neurons to produce ␣-melano-
cyte–stimulating hormone (␣-MSH). This directly

Journal of Renal Nutrition, Vol 17, No 1 ( January), 2007: pp 57-61 57

Descargado para Anonymous User (n/a) en Universidad Nacional Autonoma de Mexico de ClinicalKey.es por Elsevier en julio 04, 2018.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2018. Elsevier Inc. Todos los derechos reservados.
58 AGUILERA ET AL

BLOOD HYPOTHALAMUS
UREMIA
CCK Ghrelin Leptin L-arginine NO
1
Renal acidosis NPY
Liquid overload nNOS / ADMA

TNF- 2 Serotonin
CSF TRP Dopamine /
Plasma TRP Serotonin ratio
(BCAA+PHE+TYP+MET)
TRH Catecholamines
Catecholamines 4
Insulin AgRP -MSH

Leptin
5 MC4-Rs
L-arginine NO NPY
3

Blood
NOS / ADMA
TNF- Brain ANOREXIA
Barrier
Figure 1. Factors implicated in the pathogenesis of uremic anorexia and its treatment. CCK, cholecystokinin;
TNF-␣, tumor necrosis factor-alpha; TRP, tryptophan; BCAA, branched chain amino acid; NO, nitric oxide; NPY,
neuropeptide Y; NOS, nitric oxide synthase; nNOS, neural nitric oxide synthase; ADMA, asymmetric dimethyl-
L-arginine; CSF, cerebrospinal fluid; TRH, tryptophan hydroxylase; AgRP, agouti-related protein; ␣-MSH,
alpha-melanocyte stimulating hormones; PHE, phenylalanine; TYP, tyrosine phosphatase; MET, methionine.
In the treatment of patients with uremic anorexia, the numbers indicate the specific sites of action: 1, CCK
antagonist; 2, anti-TNF-␣ drugs (specific antibodies, megestrol acetate, thalidomide, others); 3, increased
NPY (megestrol acetate); 4, inhibitors of tryptophan transport across the blood– brain barrier (large neutral
amino and branched chain acid inhibitors); and 5, blocking of melanocortin receptor-4 (MC4-R).

stimulates MC4-R, causing increased energy ex-
penditure and reduced food intake.5 High plasma
levels of insulin, leptin, peptide YY3-36 (PYY3-36)
from the colon, and possibly other uremic toxins
induce MC4-R stimulation (Fig 1).6
Signals from GIT and liver reach the hypothal-
amus through 2 routes: through the peripheral
nerves (mainly the vagus) and via the bloodstream
as carbohydrates, amino acids, peptide, hor-
mones, nitric oxide (NO), and cytokines. Two
main neuropeptides, cholecystokinin (CCK) and
NPY, have been implicated in central appetite
control. CCK is a recognized anorexigen agent,7
and NPY is the most potent orexigen known.8
Cytokines (tumor necrosis factor [TNF]-␣ and
interleukin [IL]-1) are released during infection
or malignant processes9 and are accumulated in
dialysis patients.10 Nine TNF-␣ molecular frag-
ments have been isolated, each with a different
action. The 69 –100 fragment has suppressive
effects on food intake.11 IL-1 may also contribute
to anorexigen effects of CCK and TNF-␣.12
On the other hand, substances such as brain
amino acids and NO are implicated in peripheral
and central appetite control. During gastric and
preabsorptive phases, changes in the plasma
amino acid profile influence peripheral food in-
take. Additionally, contact between dietary
amino acids and GIT receptors stimulates CCK
release.13 In the postabsorptive phase, changes in
plasma amino acid concentrations also induce
satiety.7 Centrally, some amino acids can act as
neurotransmitters or precursors of a neurotrans-
mitter, inducing hunger or satiety.14 Catechol-
amine and serotonin pathways appear to be in-
volved in the hypothalamic regulation of feeding.
Catecholamine synthesis is influenced by brain
levels of its precursor, tyrosine. Serotonin is syn-
thesized in the brain from its precursor, trypto-
phan. Increasing brain serotonin activity is asso-
ciated with reduced food intake. In the regulation
of eating behavior, 2 factors play a pivotal role—
concentration of free tryptophan (not bound to
albumin) (FTRP) and molar ratio between
FTRP and other plasma large neutral amino acids
(LNAAs). LNAAs and branched chain amino
acids (BCCAs) are able to compete with trypto-
phan for brain entry.14

Descargado para Anonymous User (n/a) en Universidad Nacional Autonoma de Mexico de ClinicalKey.es por Elsevier en julio 04, 2018.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2018. Elsevier Inc. Todos los derechos reservados.
 BRAIN ACTIVATION IN UREMIC ANOREXIA
Table 1. Possible Disorders in Brain Appetite
Regulation in Uremic Patients
● Disturbances in the peripheral and autonomic nervous
system (axonal vagus nerve degeneration). The vagus
nerve is responsible for transporting satiety or feeding
sensation from the gastrointestinal tract to the brain.
● High plasma levels of anorexigen substances able to
cross the blood– brain barrier and induce anorexia per
se. Peptides include CCK, glucagon, insulin, leptin,
cortisol release factor, pancreatic polypeptide,
␣-MSH, and PYY3-36. Cytokines (TNF-␣ and IL-1)
lower zinc and possibly NPY.*
● Lowered nNO synthesis through decreased nNOS
associated with accumulation of ADMA and high
levels of TNF-␣.
● Inactivation of TPH by NO deficiency and increased
FTRP.
● High levels of FTRP (producing increased serotonin
synthesis).
● Imbalance in brain amino acids (high
FTRP/LNAA-BCCA ratio).
● Sympathetic hyperactivity with high levels of
dopamine, norepinephrine, and serotonin.
● Disturbances in the regulation of MC4-R.
Abbreviations: CCK, cholecystokinin; ␣-MSH, alpha-mel-
anocyte stimulating hormone; PYY3-36, peptide YY3-36;
TNF-␣, tumoral necrosis factor-alpha; IL-1, interleukin-1;
NPY, neuropeptide Y; nNO, neural nitric oxide; nNOS, neu-
ral NO synthase; ADMA, asymmetric dimethyl-L-arginine;
TPH, tryptophan hydroxylase; FTRP, free tryptophan; LNAA,
plasma large neutral amino acid; BCCA, branched chain
amino acid; MC4-R, melanocortin receptor-4.
*Other groups found high plasma levels. In our study,27
NPY was normal in 80% of cases, and relatively low
values were found in anorexic patients on peritoneal
dialysis.
NO, an endothelium-released factor synthe-
sized from the amino acid L-arginine by a specific
synthase (nitric oxide synthase [NOS]), partici-
pates in brain development and function. Exper-
imentally, the administration of NG-nitro-L-ar-
ginine methyl ester (L-NAME), an inhibitor of
NOS, reduces food intake in rats.15 Interesting
observations have shown an interaction between
brain NO levels and serotonin synthesis.15 Brain
NO inactivates brain tryptophan hydroxylase
(TPH), decreasing brain tryptophan and subse-
quently serotonin and catecholamine levels. Both
dopamine and norepinephrine increase the avail-
ability of brain tryptophan, initiating a vicious
circle.16 In uremia, NO deficiency has also been
implicated in the pathogenesis of cardiovascular
complications.17 Table 1 lists the CNS disorders
that are responsible for uremic anorexia.
Descargado para Anonymous User (n/a) en Universidad Nacional Autonoma de Mexico de ClinicalKey.es por Elsevier en julio 04, 2018.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2018. Elsevier Inc. Todos los derechos reservados.
59
Cytokines and Uremic Anorexia
IL-1 and TNF-␣ have been shown to interfere
with tryptophan and serotonin turnover. It is
therefore possible that, by interfering with the
mechanism that regulates the plasma tryptophan
pool or by increasing brain serotonin release, IL-1
and TNF-␣ may participate in uremic serotonin-
induced anorexia.9,14 In support of this hypoth-
esis, other groups10 have reported high TNF-␣
plasma levels in patients on peritoneal dialysis
(PD). TNF-␣ plasma levels were significantly
higher in patients with anorexia and malnutri-
tion.18 Moreover, TNF-␣ is able to inhibit he-
patic albumin gene expression, thereby contrib-
uting to dialysis protein malnutrition.19
NO and Uremic Anorexia
Accumulation of endogenous NO inhibitors
(asymmetric dimethyl-L-arginine [ADMA]) has
been described in uremic patients.20 Experimen-
tally, the administration of L-NAME increases
blood pressure and brain serotonin concentration,
induces gastric distention, and promotes and fa-
cilitates oxidation of L-arginine to ornithine.15
Also, TNF-␣ decreases NOS levels through se-
lective destabilization of mRNA transcription,
and it enhances sympathetic activity, thus induc-
ing anorexia again.21 Therefore, uremic NO de-
ficiency via inactivation of brain TPH may be
another cause of anorexia.16
Leptin and Uremic Anorexia
Leptin, a 16-kDa protein that is produced by
adipocytes, regulates body fat through a central
satiety effect. Hyperleptinemia, possibly caused
by uremic retention, hyperproduction, or both,
has been described in cases of uremia. It has been
suggested that leptin may be involved in malnu-
trition of dialysis patients. A leptin receptor dis-
order has been noted in an obese population, and
acquired leptin receptor disorders (ie, resistance
to insulin or parathormone) may be speculated in
uremic individuals. Uremic patients may also
have normal sensibility to the hypothalamic lep-
tin receptor. As a consequence, the uremic hy-
perleptinemia may up-regulate the hypothalamic
leptin receptor. The mechanism by which leptin
induces appetite suppression is reducing the hy-
pothalamic NPY levels and increasing the sym-
pathetic activity with hyperinsulinaemia.22 Con-
60
sistent with this hypothesis is the sympathetic
hyperactivity (ie, dopamine, norepinephrine, se-
rotonin) described in uremic patients.23 More-
over, in rats, injection of leptin decreases brain
nNOS, thyrotropin-releasing hormone, and cor-
ticotropin-releasing hormone mRNA in para-
ventricular and supraoptic nuclei, with conse-
quent increases in diencephalic serotonin
content.24 Leptin also acts as a proinflammatory
molecule.22
Plasma and Brain Amino Acids
and Uremic Anorexia
Substantial evidence suggests that changes in
plasma amino acid profile affect brain or neuro-
transmitter synthesis.14 A significant change in
unbound plasma tryptophan and/or an increase in
tryptophan competing amino acids results in se-
rotonergic hyperactivity and anorexia. These ob-
servations have contributed to the tryptophan–
serotonin hypothesis, which has been proved in
rats.14 Changes in the central amino acid profile,
which have been observed in uremic humans14,25
and rats, consist of low glutamine and ␥-ami-
nobutyric acid (GABA); high levels of glycine
and free tryptophan (with reduced total plasma
tryptophan); elevated phenylalanine/tyrosine ra-
tio; increases in 5-hydroxyindoleacetic and ho-
movanillic acids and their ratio; and increased
levels of alanine, lysine, arginine, histidine,
3-methyl-histidine, citrulline, and ornithine.25,26
Evidence favors the possibility that hypothalamic
serotonin has a greater effect in reducing carbo-
hydrates with respect to protein or fat ingestion.
Moreover, long-term serotonin administration
induces an important reduction in all macronu-
trients under experimental conditions.27
High plasma and intracerebral concentrations
of FTPR and resultant increases in serotonin
enhance the serotonin/dopamine ratio. This phe-
nomenon may be perpetuated through high con-
centrations of IL-1, TNF-␣, CCK, leptin, cat-
echolamines, and insulin; by metabolic acidosis;
and by low levels of NO induced by high ADMA
concentration (Fig 1). Leptin induces hyperinsu-
linemia by causing insulin resistance, sympathetic
hyperactivity, and decreased NPY, whereas NPY
decreases NOS activity and NO production. Low
NO concentrations induce an increase in TPH,
and consequently, an increase in FTRP, with
decreases in LNAA noted. On the other hand,
Descargado para Anonymous User (n/a) en Universidad Nacional Autonoma de Mexico de ClinicalKey.es por Elsevier en julio 04, 2018.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2018. Elsevier Inc. Todos los derechos reservados.
AGUILERA ET AL
proinflammatory molecules (IL-1 and TNF-␣)
accumulated through renal failure or overpro-
duced by inflamed tissues or overhydration28
augment renal acidosis, hyperinsulinemia, sympa-
thetic activity, and FTRP, with decreases re-
ported in LNAA and NOS activity. High CCK
plasma levels reveal a synergistic anorexigen effect
with IL-1, caused by direct induction of decreases
in LNAA (Fig 1).
Recently, a very important disorder at the end
of the hunger–satiety pathway (MC4-R) has
been described in uremic mice with leptin recep-
tor deficiency (db/db) and in MC4-R knockout
mice (MC4-RKO).29 Cheung and colleagues29
injected AGRP into mice with subtotal nephrec-
tomy in the lateral ventricle, inducing increased
food intake and body growth and a decline in
resting metabolic rate, which suggests that uremia
at particular stages may cause a defect in the
ability of AGRP to block MC4-Rs. Another
important conclusion of this article is that leptin,
by signaling its receptor, is an important cause of
uremic cachexia; uremic mice with leptin recep-
tor deficiency (db/db) grew in a similar manner to
sham-operated, pair-fed (db/db) mice. However,
it is impossible to exclude the possibility that
other mechanisms such as acidosis and inflamma-
tion may act in an independent manner, thereby
inducing cachexia. All these findings should be
connected to the tryptophan–serotonin disorder
hypothesis proposed by our group.30 We believe
that evidence implies a connection between the
brain hyperserotoninergic-like syndrome or tryp-
tophan–serotonin disorder hypothesis and the
disorders described by Cheung et al29:
1. Serotonin is the most important regulator
of MC4-R expression. In fact, serotonin
reuptake inhibitors and MC4-R antago-
nists share antidepression and antianxiety
effects.31
2. Serotonin shows an acute and direct effect
on AGRP release, favoring MC4-R over-
expression and causing anorexia.32
3. Ghrelin, an orexigen stomach hormone,
provides negative feedback to brain
serotonin.33
In summary, all these systems are confluent in
inducing and/or perpetuating hyperserotoniner-
gic brain status, which translates into anorexia.
Uremic anorexia is a complex complication
associated with malnutrition and high levels of
 BRAIN ACTIVATION IN UREMIC ANOREXIA
morbidity and mortality. Several uremia-acquired
disorders in the CNS such as high cerebrospinal
fluid levels of anorexigen substances and disorders
in appetite regulator receptors may explain the
lack of appetite. These recent findings open pos-
sibilities for new therapeutic targets.
References
1. Bergström J: Appetite in CAPD patients. Perit Dial 16:
S181-S184, 1996 (suppl 1)
2. Owen W, Lew N, Luí Y, et al: The urea reduction ratio
and serum albumin concentration as predictors of mortality in
patients undergoing hemodialysis. N Engl J Med 329:1001-1006,
1993
3. Aguilera A, Selgas R, Diéz JJ, et al: Anorexia in end-stage
renal disease: Pathophysiology and treatment. Expert Opin Phar-
macother 2:1825-1838, 2001
4. Stricker EM: Biological bases of hunger and satiety: Ther-
apeutic implications. Nutr Rev 42:333-340, 1984
5. Butler AA, Marks DL, Fan W, et al: Melanocortin-4
receptor is required for acute homeostatic responses to increase
dietary fat. Nat Neurosci 4:605-611, 2001
6. Batterham RL, Cowley MA, Small CJ, et al: Gut hormone
PYY3-36 physiologically inhibits food intake. Nature 418:650-
654, 2002
7. Anderson GH, Li ETS, Anthony SP, et al: Dissociation
between plasma and brain amino acid profiles and short-term
food intake in the rat. Am J Physiol 35:R1675-R1686, 1994
8. Dube MG, Xu B, Crowley WR, et al: Evidence that
neuropetide Y is a physiological signal of normal food intake.
Brain Res 646:341-344, 1994
9. Plata-Salamán C: Cytokines and feeding suppression: An
integrative view from neurologic to molecular levels. Nutrition
11:674-677, 1995 (suppl 5)
10. MacDonald C, Rush D, Bernstein K, et al: Production of
tumoral necrosis factor in hemodialysis. Nephron 65:273-277,
1993
11. Kapás L, Hong L, Cady AB, et al: Somnogenic, pyro-
genic, and anorectic activities of tumor necrosis factor alpha and
TNF-␣ fragments. Am J Physiol 263:R708-R715, 1993
12. Treget EE, Yu YM, Zhong S, et al: Role of interleukin 1
and tumor necrosis factor in energy metabolism in rabbits. Am J
Physiol 255:E760-E768, 1988
13. Bellinger LL, Williams FE, Rogers QR, et al: Liver
denervation attenuate the hypophagia produced by an imbal-
anced acid diet. Physiol Behav 59:925-929, 1996
14. Cangiano C, Laviano A, Muscaritoli M, et al: Cancer
anorexia: New pathogenic and therapeutic insights. Nutrition
12:S48-S50, 1996
15. Squadrito F, Calapai D, Altavilla D, et al: Central serotoner-
gic system involvement in the anorexia induced by NG-nitro-L-
arginine, an inhibitor of nitric oxide synthase. Eur J Pharmacol
255:51-55, 1994
16. Kuhn DM, Arthur R: Molecular mechanism of the inac-
tivation of tryptophan hydroxylase by nitric oxide: Attack on
critical sulfhydryls that spare the enzyme iron center. J Neurosci
17:7245-7251, 1997
Descargado para Anonymous User (n/a) en Universidad Nacional Autonoma de Mexico de ClinicalKey.es por Elsevier en julio 04, 2018.
Para uso personal exclusivamente. No se permiten otros usos sin autorización. Copyright ©2018. Elsevier Inc. Todos los derechos reservados.
61
17. Ritz E, Villance P, Nowicki M: The effect of malnutri-
tion on cardiovascular mortality in dialysis patients: Is L-arginine
the Answer? Nephol Dial Transplant 9:129-130, 1994
18. Aguilera A, Codoceo R, Selgas R, et al: Anorexigen
(TNF-␣, cholecystokinin) and orexigen (neuropeptide Y) plasma
levels in peritoneal dialysis (PD) patients: Their relationship with
nutritional parameters. Nephrol Dial Transpl 13:1476-1483,
1998
19. Brenner D, Buck M, Feitelberg S, et al: Tumor necrosis
factor alpha inhibits albumin gene expression in a murine model
of cachexia. J Clin Invest 85:248-255, 1990
20. Vallance P, Leone A, Calver A, et al: Accumulation of an
endogenous inhibitor nitric oxide synthesis in chronic renal
failure. Lancet 339:572-575, 1992
21. Ando T, Dunn AJ: Mouse tumor necrosis factor alpha
increases brain tryptophan concentrations and norepinephrine
metabolism while activating the HPA axis in nice. Neuroimmu-
nomodulation 6:319-329, 1999
22. Stenvinkel P: Leptin—A new hormone of definite interest
for the nephrologist. Nephrol Dial Transplant 13:1099-1101, 1998
23. Converse RL, Jacobsen TN, Toto RD, et al: Sympha-
thetic overactivity in patients with chronic renal failure. N Engl
J Med 327:1912-1918, 1992
24. Isse T, Ueta Y, Serino R, et al: Effects of leptin on
fasting-induced inhibition of neural nitric oxide synthase mRNA
in paraventricular and supraoptic nuclei of rats. Brain Res 846:
229-235, 1999
25. Laviano A, Cangiano C, Preziosa I, et al: Plasma trypto-
phan and anorexia in liver cirrhosis. Int J Eating Disord 21:181-
186, 1996
26. Siassi F, Wang M, Kopple JD, et al: Plasma tryptophan
levels and brain serotonin metabolism in chronically uremic rats.
J Nutr 107:840-845, 1977
27. Leibowitz SF, Alexander JT: Hypothalamic serotonin in
control of eating behavior, meal size, and body weight. Biol
Psychiatry 44:851-864, 1998
28. Niebauer J, Volk HD, Kemp M, et al: Endotoxin and
immune activation in chronic heart failure: A prospective cohort
study. Lancet 353:1838-1842, 1999
29. Cheung W, Yu PX, Little BM, et al: Role of leptin and
melanocortin signalling in uremia-associated cachexia. J Clin
Invest 115:1659-1665, 2005
30. Aguilera A, Codoceo R, Bajo MA, et al: Eating behavior
disorders in uremia: A question of balance in appetite regulation.
Semin Dial 17:44-52, 2004
31. Chaki S, Hirota S, Funakoshi T, et al: Anxiolytic-like and
antidepressant-like activities of MCLO129 (1-((S)-2-(4-fluoro-
phenyl)-2-(4-isopropylpiperadin-1-yl) ethyl)-4-(2-methoxynaph-
thalen-1-yl) butyl) piperazine), a novel and potent nonpeptide
antagonist of the melanocortin-4 receptor. J Pharmacol Exp Therap
304:818-826, 2003
32. Li JY, Finniss S, Yang YK, et al: Agouti-related protein–
like immunoreactivity: Characterization of release from hypo-
thalamic tissue and presence in serum. Endocrinology 141:1942-
1950, 2000
33. Nonogaki K, Ohashi-Nozue K, Oka Y: A negative feed-
back system between brain serotonin systems and plasma active
ghrelin levels has been described in mice. Biochem Biophys Res
Commun 341:703-707, 2006