Background/Aims: Nesfatin-1, processed from nucleobindin-2 (NUCB2), is a potent anorexigenic peptide being expressed in rodent hypothalamic nuclei and involved in the regulation of feeding behavior and body weight in animals. The present study aimed to investigate NUCB2/nesfatin-1 protein expression in the human hypothalamus as well as its correlation with body weight. Methods: Sections of hypothalamus and adjacent cholinergic basal forebrain nuclei, including the nucleus basalis of Meynert (NBM) and the diagonal band of Broca (DBB), from 25 autopsy cases (17 males, 8 females; 8 lean, 9 overweight, 8 obese) were examined using immunohistochemistry and double immunofluorescence labeling. Results: Prominent NUCB2/nesfatin-1 immunoexpression was detected in supraoptic, paraventricular, and infundibular nuclei, lateral hypothalamic area (LHA)/perifornical region, and NBM/DBB. NUCB2/nesfatin-1 was found to extensively colocalize with (a) oxytocin and vasopressin in paraventricular and supraoptic nuclei, (b) melanin-concentrating hormone in the LHA, and (c) cocaine- and amphetamine-regulated transcript in infundibular and paraventricular nuclei and LHA. Interestingly, in the LHA, NUCB2/nesfatin-1 protein expression was significantly decreased in obese, compared with lean (p < 0.01) and overweight (p < 0.05) subjects. Conclusions: The findings of the present study are suggestive of a potential role for NUCB2/nesfatin-1 as an integral regulator of food intake and energy homeostasis in the human hypothalamus. In the LHA, an appetite- and reward-related brain area, reduced NUCB2/nesfatin-1 immunoexpression may contribute to dysregulation of homeostatic and/or hedonic feeding behavior and obesity. NUCB2/nesfatin-1 localization in NBM/DBB might imply its participation in the neuronal circuitry controlling cognitive influences on food intake and give impetus towards unraveling additional biological actions of NUCB2/nesfatin-1 in human neuronal networks.

1.
Rolls
ET
.
The neurophysiology of feeding
.
Int J Obes
.
1984
;
8
Suppl 1
:
139
50
.
[PubMed]
0307-0565
2.
Richard
D
.
Cognitive and autonomic determinants of energy homeostasis in obesity
.
Nat Rev Endocrinol
.
2015
Aug
;
11
(
8
):
489
501
.
[PubMed]
1759-5029
3.
Oh-I
S
,
Shimizu
H
,
Satoh
T
,
Okada
S
,
Adachi
S
,
Inoue
K
, et al
Identification of nesfatin-1 as a satiety molecule in the hypothalamus
.
Nature
.
2006
Oct
;
443
(
7112
):
709
12
.
[PubMed]
0028-0836
4.
Dore
R
,
Levata
L
,
Lehnert
H
,
Schulz
C
.
Nesfatin-1: functions and physiology of a novel regulatory peptide
.
J Endocrinol
.
2017
Jan
;
232
(
1
):
R45
65
.
[PubMed]
0022-0795
5.
Brailoiu
GC
,
Dun
SL
,
Brailoiu
E
,
Inan
S
,
Yang
J
,
Chang
JK
, et al
Nesfatin-1: distribution and interaction with a G protein-coupled receptor in the rat brain
.
Endocrinology
.
2007
Oct
;
148
(
10
):
5088
94
.
[PubMed]
0013-7227
6.
Foo
KS
,
Brismar
H
,
Broberger
C
.
Distribution and neuropeptide coexistence of nucleobindin-2 mRNA/nesfatin-like immunoreactivity in the rat CNS
.
Neuroscience
.
2008
Oct
;
156
(
3
):
563
79
.
[PubMed]
0306-4522
7.
Goebel
M
,
Stengel
A
,
Wang
L
,
Lambrecht
NW
,
Taché
Y
.
Nesfatin-1 immunoreactivity in rat brain and spinal cord autonomic nuclei
.
Neurosci Lett
.
2009
Mar
;
452
(
3
):
241
6
.
[PubMed]
0304-3940
8.
Goebel-Stengel
M
,
Wang
L
,
Stengel
A
,
Taché
Y
.
Localization of nesfatin-1 neurons in the mouse brain and functional implication
.
Brain Res
.
2011
Jun
;
1396
:
20
34
.
[PubMed]
0006-8993
9.
Goebel-Stengel
M
,
Wang
L
.
Central and peripheral expression and distribution of NUCB2/nesfatin-1
.
Curr Pharm Des
.
2013
;
19
(
39
):
6935
40
.
[PubMed]
1381-6128
10.
Kim
J
,
Chung
Y
,
Kim
H
,
Im
E
,
Lee
H
,
Yang
H
.
The Tissue Distribution of Nesfatin-1/NUCB2 in Mouse
.
Dev Reprod
.
2014
Dec
;
18
(
4
):
301
9
.
[PubMed]
2465-9525
11.
Stengel
A
,
Goebel
M
,
Yakubov
I
,
Wang
L
,
Witcher
D
,
Coskun
T
, et al
Identification and characterization of nesfatin-1 immunoreactivity in endocrine cell types of the rat gastric oxyntic mucosa
.
Endocrinology
.
2009
Jan
;
150
(
1
):
232
8
.
[PubMed]
0013-7227
12.
Stengel
A
,
Hofmann
T
,
Goebel-Stengel
M
,
Lembke
V
,
Ahnis
A
,
Elbelt
U
, et al
Ghrelin and NUCB2/nesfatin-1 are expressed in the same gastric cell and differentially correlated with body mass index in obese subjects
.
Histochem Cell Biol
.
2013
Jun
;
139
(
6
):
909
18
.
[PubMed]
0948-6143
13.
Ramanjaneya
M
,
Chen
J
,
Brown
JE
,
Tripathi
G
,
Hallschmid
M
,
Patel
S
, et al
Identification of nesfatin-1 in human and murine adipose tissue: a novel depot-specific adipokine with increased levels in obesity
.
Endocrinology
.
2010
Jul
;
151
(
7
):
3169
80
.
[PubMed]
0013-7227
14.
Riva
M
,
Nitert
MD
,
Voss
U
,
Sathanoori
R
,
Lindqvist
A
,
Ling
C
, et al
Nesfatin-1 stimulates glucagon and insulin secretion and beta cell NUCB2 is reduced in human type 2 diabetic subjects
.
Cell Tissue Res
.
2011
Dec
;
346
(
3
):
393
405
.
[PubMed]
0302-766X
15.
Gonzalez
R
,
Tiwari
A
,
Unniappan
S
.
Pancreatic beta cells colocalize insulin and pronesfatin immunoreactivity in rodents
.
Biochem Biophys Res Commun
.
2009
Apr
;
381
(
4
):
643
8
.
[PubMed]
0006-291X
16.
García-Galiano
D
,
Pineda
R
,
Ilhan
T
,
Castellano
JM
,
Ruiz-Pino
F
,
Sánchez-Garrido
MA
, et al
Cellular distribution, regulated expression, and functional role of the anorexigenic peptide, NUCB2/nesfatin-1, in the testis
.
Endocrinology
.
2012
Apr
;
153
(
4
):
1959
71
.
[PubMed]
0013-7227
17.
Pan
W
,
Hsuchou
H
,
Kastin
AJ
.
Nesfatin-1 crosses the blood-brain barrier without saturation
.
Peptides
.
2007
Nov
;
28
(
11
):
2223
8
.
[PubMed]
0196-9781
18.
Price
TO
,
Samson
WK
,
Niehoff
ML
,
Banks
WA
.
Permeability of the blood-brain barrier to a novel satiety molecule nesfatin-1
.
Peptides
.
2007
Dec
;
28
(
12
):
2372
81
.
[PubMed]
0196-9781
19.
Tan
BK
,
Hallschmid
M
,
Kern
W
,
Lehnert
H
,
Randeva
HS
.
Decreased cerebrospinal fluid/plasma ratio of the novel satiety molecule, nesfatin-1/NUCB-2, in obese humans: evidence of nesfatin-1/NUCB-2 resistance and implications for obesity treatment
.
J Clin Endocrinol Metab
.
2011
Apr
;
96
(
4
):
E669
73
.
[PubMed]
0021-972X
20.
Stengel
A
,
Goebel
M
,
Wang
L
,
Rivier
J
,
Kobelt
P
,
Mönnikes
H
, et al
Central nesfatin-1 reduces dark-phase food intake and gastric emptying in rats: differential role of corticotropin-releasing factor2 receptor
.
Endocrinology
.
2009
Nov
;
150
(
11
):
4911
9
.
[PubMed]
0013-7227
21.
Maejima
Y
,
Sedbazar
U
,
Suyama
S
,
Kohno
D
,
Onaka
T
,
Takano
E
, et al
Nesfatin-1-regulated oxytocinergic signaling in the paraventricular nucleus causes anorexia through a leptin-independent melanocortin pathway
.
Cell Metab
.
2009
Nov
;
10
(
5
):
355
65
.
[PubMed]
1550-4131
22.
Shimizu
H
,
Oh-I
S
,
Hashimoto
K
,
Nakata
M
,
Yamamoto
S
,
Yoshida
N
, et al
Peripheral administration of nesfatin-1 reduces food intake in mice: the leptin-independent mechanism
.
Endocrinology
.
2009
Feb
;
150
(
2
):
662
71
.
[PubMed]
0013-7227
23.
Atsuchi
K
,
Asakawa
A
,
Ushikai
M
,
Ataka
K
,
Tsai
M
,
Koyama
K
, et al
Centrally administered nesfatin-1 inhibits feeding behaviour and gastroduodenal motility in mice
.
Neuroreport
.
2010
Oct
;
21
(
15
):
1008
11
.
[PubMed]
0959-4965
24.
Goebel
M
,
Stengel
A
,
Wang
L
,
Taché
Y
.
Central nesfatin-1 reduces the nocturnal food intake in mice by reducing meal size and increasing inter-meal intervals
.
Peptides
.
2011
Jan
;
32
(
1
):
36
43
.
[PubMed]
0196-9781
25.
Stengel
A
,
Goebel-Stengel
M
,
Wang
L
,
Kato
I
,
Mori
M
,
Taché
Y
.
Nesfatin-1(30-59) but not the N- and C-terminal fragments, nesfatin-1(1-29) and nesfatin-1(60-82) injected intracerebroventricularly decreases dark phase food intake by increasing inter-meal intervals in mice
.
Peptides
.
2012
Jun
;
35
(
2
):
143
8
.
[PubMed]
0196-9781
26.
Chen
X
,
Dong
J
,
Jiang
ZY
.
Nesfatin-1 influences the excitability of glucosensing neurons in the hypothalamic nuclei and inhibits the food intake
.
Regul Pept
.
2012
Aug
;
177
(
1-3
):
21
6
.
[PubMed]
0167-0115
27.
Li
ZL
,
Xu
L
,
Sun
XR
,
Guo
FF
,
Gong
YL
,
Gao
SL
.
Central nesfatin-1 influences the excitability of ghrelin-responsive gastric distension neurons in the arcuate nucleus and reduces gastric motility in rats
.
Eur J Neurosci
.
2013
Dec
;
38
(
11
):
3636
43
.
[PubMed]
0953-816X
28.
Sedbazar
U
,
Ayush
EA
,
Maejima
Y
,
Yada
T
.
Neuropeptide Y and α-melanocyte-stimulating hormone reciprocally regulate nesfatin-1 neurons in the paraventricular nucleus of the hypothalamus
.
Neuroreport
.
2014
Dec
;
25
(
18
):
1453
8
.
[PubMed]
0959-4965
29.
Guo
FF
,
Xu
L
,
Gao
SL
,
Sun
XR
,
Li
ZL
,
Gong
YL
.
The effects of nesfatin-1 in the paraventricular nucleus on gastric motility and its potential regulation by the lateral hypothalamic area in rats
.
J Neurochem
.
2015
Feb
;
132
(
3
):
266
75
.
[PubMed]
0022-3042
30.
Xu
L
,
Wang
H
,
Gong
Y
,
Pang
M
,
Sun
X
,
Guo
F
, et al
Nesfatin-1 regulates the lateral hypothalamic area melanin-concentrating hormone-responsive gastric distension-sensitive neurons and gastric function via arcuate nucleus innervation
.
Metabolism
.
2017
Feb
;
67
:
14
25
.
[PubMed]
0026-0495
31.
Kohno
D
,
Nakata
M
,
Maejima
Y
,
Shimizu
H
,
Sedbazar
U
,
Yoshida
N
, et al
Nesfatin-1 neurons in paraventricular and supraoptic nuclei of the rat hypothalamus coexpress oxytocin and vasopressin and are activated by refeeding
.
Endocrinology
.
2008
Mar
;
149
(
3
):
1295
301
.
[PubMed]
0013-7227
32.
Miyata
S
,
Yamada
N
,
Kawada
T
.
Possible involvement of hypothalamic nucleobindin-2 in hyperphagic feeding in Tsumura Suzuki obese diabetes mice
.
Biol Pharm Bull
.
2012
;
35
(
10
):
1784
93
.
[PubMed]
0918-6158
33.
García-Galiano
D
,
Navarro
VM
,
Gaytan
F
,
Tena-Sempere
M
.
Expanding roles of NUCB2/nesfatin-1 in neuroendocrine regulation
.
J Mol Endocrinol
.
2010
Nov
;
45
(
5
):
281
90
.
[PubMed]
0952-5041
34.
Swaab
DF
.
Handbook of Clinical Neurology. The Human Hypothalamus: Basic and Clinical Aspects. I. Nuclei of the Human Hypothalamus
.
Volume 79
.
Amsterdam
:
Elsevier
;
2003
. pp.
39
59
.
35.
Reizes
O
,
Lincecum
J
,
Wang
Z
,
Goldberger
O
,
Huang
L
,
Kaksonen
M
, et al
Transgenic expression of syndecan-1 uncovers a physiological control of feeding behavior by syndecan-3
.
Cell
.
2001
Jul
;
106
(
1
):
105
16
.
[PubMed]
0092-8674
36.
Yi
SS
,
Hwang
IK
,
Kim
YN
,
Kim
IY
,
Pak
SI
,
Lee
IS
, et al
Enhanced expressions of arginine vasopressin (Avp) in the hypothalamic paraventricular and supraoptic nuclei of type 2 diabetic rats
.
Neurochem Res
.
2008
May
;
33
(
5
):
833
41
.
[PubMed]
0364-3190
37.
Chiocchio
SR
,
Gallardo
MG
,
Louzan
P
,
Gutnisky
V
,
Tramezzani
JH
.
Melanin-concentrating hormone stimulates the release of luteinizing hormone-releasing hormone and gonadotropins in the female rat acting at both median eminence and pituitary levels
.
Biol Reprod
.
2001
May
;
64
(
5
):
1466
72
.
[PubMed]
0006-3363
38.
Hunter
RG
,
Lim
MM
,
Philpot
KB
,
Young
LJ
,
Kuhar
MJ
.
Species differences in brain distribution of CART mRNA and CART peptide between prairie and meadow voles
.
Brain Res
.
2005
Jun
;
1048
(
1-2
):
12
23
.
[PubMed]
0006-8993
39.
Mitrofanis
J
.
Some certainty for the “zone of uncertainty”? Exploring the function of the zona incerta
.
Neuroscience
.
2005
;
130
(
1
):
1
15
.
[PubMed]
0306-4522
40.
Arendt
T
,
Bigl
V
,
Tennstedt
A
,
Arendt
A
.
Neuronal loss in different parts of the nucleus basalis is related to neuritic plaque formation in cortical target areas in Alzheimer’s disease
.
Neuroscience
.
1985
Jan
;
14
(
1
):
1
14
.
[PubMed]
0306-4522
41.
Stengel
A
,
Taché
Y
.
Nesfatin-1—role as possible new potent regulator of food intake
.
Regul Pept
.
2010
Aug
;
163
(
1-3
):
18
23
.
[PubMed]
0167-0115
42.
Fort
P
,
Salvert
D
,
Hanriot
L
,
Jego
S
,
Shimizu
H
,
Hashimoto
K
, et al
The satiety molecule nesfatin-1 is co-expressed with melanin concentrating hormone in tuberal hypothalamic neurons of the rat
.
Neuroscience
.
2008
Jul
;
155
(
1
):
174
81
.
[PubMed]
0306-4522
43.
Pałasz
A
,
Krzystanek
M
,
Worthington
J
,
Czajkowska
B
,
Kostro
K
,
Wiaderkiewicz
R
, et al
Nesfatin-1, a unique regulatory neuropeptide of the brain
.
Neuropeptides
.
2012
Jun
;
46
(
3
):
105
12
.
[PubMed]
0143-4179
44.
Nakata
M
,
Gantulga
D
,
Santoso
P
,
Zhang
B
,
Masuda
C
,
Mori
M
, et al
Paraventricular NUCB2/Nesfatin-1 Supports Oxytocin and Vasopressin Neurons to Control Feeding Behavior and Fluid Balance in Male Mice
.
Endocrinology
.
2016
Jun
;
157
(
6
):
2322
32
.
[PubMed]
0013-7227
45.
Spetter
MS
,
Hallschmid
M
.
Current findings on the role of oxytocin in the regulation of food intake
.
Physiol Behav
.
2017
Jul
;
176
:
31
9
.
[PubMed]
0031-9384
46.
Ott
V
,
Finlayson
G
,
Lehnert
H
,
Heitmann
B
,
Heinrichs
M
,
Born
J
, et al
Oxytocin reduces reward-driven food intake in humans
.
Diabetes
.
2013
Oct
;
62
(
10
):
3418
25
.
[PubMed]
0012-1797
47.
Lawson
EA
,
Marengi
DA
,
DeSanti
RL
,
Holmes
TM
,
Schoenfeld
DA
,
Tolley
CJ
.
Oxytocin reduces caloric intake in men
.
Obesity (Silver Spring)
.
2015
May
;
23
(
5
):
950
6
.
[PubMed]
1930-7381
48.
Langhans
W
,
Delprete
E
,
Scharrer
E
.
Mechanisms of vasopressin’s anorectic effect
.
Physiol Behav
.
1991
Jan
;
49
(
1
):
169
76
.
[PubMed]
0031-9384
49.
Yosten
GL
,
Redlinger
L
,
Samson
WK
.
Evidence for a role of endogenous nesfatin-1 in the control of water drinking
.
J Neuroendocrinol
.
2012
Jul
;
24
(
7
):
1078
84
.
[PubMed]
0953-8194
50.
Saper
CB
,
Chou
TC
,
Elmquist
JK
.
The need to feed: homeostatic and hedonic control of eating
.
Neuron
.
2002
Oct
;
36
(
2
):
199
211
.
[PubMed]
0896-6273
51.
Presse
F
,
Nahon
JL
,
Fischer
WH
,
Vale
W
.
Structure of the human melanin concentrating hormone mRNA
.
Mol Endocrinol
.
1990
Apr
;
4
(
4
):
632
7
.
[PubMed]
0888-8809
52.
Lau
J
,
Farzi
A
,
Qi
Y
,
Heilbronn
R
,
Mietzsch
M
,
Shi
YC
, et al
CART neurons in the arcuate nucleus and lateral hypothalamic area exert differential controls on energy homeostasis
.
Mol Metab
.
2018
Jan
;
7
:
102
18
.
[PubMed]
2212-8778
53.
Inhoff
T
,
Stengel
A
,
Peter
L
,
Goebel
M
,
Taché
Y
,
Bannert
N
, et al
Novel insight in distribution of nesfatin-1 and phospho-mTOR in the arcuate nucleus of the hypothalamus of rats
.
Peptides
.
2010
Feb
;
31
(
2
):
257
62
.
[PubMed]
0196-9781
54.
Georgescu
D
,
Sears
RM
,
Hommel
JD
,
Barrot
M
,
Bolaños
CA
,
Marsh
DJ
, et al
The hypothalamic neuropeptide melanin-concentrating hormone acts in the nucleus accumbens to modulate feeding behavior and forced-swim performance
.
J Neurosci
.
2005
Mar
;
25
(
11
):
2933
40
.
[PubMed]
0270-6474
55.
Stuber
GD
,
Wise
RA
.
Lateral hypothalamic circuits for feeding and reward
.
Nat Neurosci
.
2016
Feb
;
19
(
2
):
198
205
.
[PubMed]
1097-6256
56.
Bellinger
LL
,
Bernardis
LL
.
The dorsomedial hypothalamic nucleus and its role in ingestive behavior and body weight regulation: lessons learned from lesioning studies
.
Physiol Behav
.
2002
Jul
;
76
(
3
):
431
42
.
[PubMed]
0031-9384
57.
King
BM
.
The rise, fall, and resurrection of the ventromedial hypothalamus in the regulation of feeding behavior and body weight
.
Physiol Behav
.
2006
Feb
;
87
(
2
):
221
44
.
[PubMed]
0031-9384
58.
Eriksson
KS
,
Sergeeva
O
,
Brown
RE
,
Haas
HL
.
Orexin/hypocretin excites the histaminergic neurons of the tuberomammillary nucleus
.
J Neurosci
.
2001
Dec
;
21
(
23
):
9273
9
.
[PubMed]
0270-6474
59.
Giannoni
P
,
Passani
MB
,
Nosi
D
,
Chazot
PL
,
Shenton
FC
,
Medhurst
AD
, et al
Heterogeneity of histaminergic neurons in the tuberomammillary nucleus of the rat
.
Eur J Neurosci
.
2009
Jun
;
29
(
12
):
2363
74
.
[PubMed]
0953-816X
60.
Dalton
LD
,
Grossman
SP
.
Responses to dietary adulterations in rats with zona incerta lesions
.
Physiol Behav
.
1982
Jul
;
29
(
1
):
51
60
.
[PubMed]
0031-9384
61.
Zhang
X
,
van den Pol
AN
.
Rapid binge-like eating and body weight gain driven by zona incerta GABA neuron activation
.
Science
.
2017
May
;
356
(
6340
):
853
9
.
[PubMed]
0036-8075
62.
Gao
S
,
Guo
F
,
Sun
X
,
Zhang
N
,
Gong
Y
,
Xu
L
.
The inhibitory effects of nesfatin-1 in ventromedial hypothalamus on gastric function and its regulation by nucleus accumbens
.
Front Physiol
.
2017
Jan
;
7
:
634
.
[PubMed]
1664-042X
63.
Boix-Trelis
N
,
Vale-Martínez
A
,
Guillazo-Blanch
G
,
Costa-Miserachs
D
,
Martí-Nicolovius
M
.
Effects of nucleus basalis magnocellularis stimulation on a socially transmitted food preference and c-Fos expression
.
Learn Mem
.
2006
Nov-Dec
;
13
(
6
):
783
93
.
[PubMed]
1072-0502
64.
Higgs
S
.
Cognitive influences on food intake: the effects of manipulating memory for recent eating
.
Physiol Behav
.
2008
Aug
;
94
(
5
):
734
9
.
[PubMed]
0031-9384
65.
Herman
AM
,
Ortiz-Guzman
J
,
Kochukov
M
,
Herman
I
,
Quast
KB
,
Patel
JM
, et al
A cholinergic basal forebrain feeding circuit modulates appetite suppression
.
Nature
.
2016
Oct
;
538
(
7624
):
253
6
.
[PubMed]
0028-0836
66.
Noreik
M
,
Kuhn
J
,
Hardenacke
K
,
Lenartz
D
,
Bauer
A
,
Bührle
CP
, et al
Changes in nutritional status after deep brain stimulation of the nucleus basalis of Meynert in Alzheimer’s disease–Results of a phase I study
.
J Nutr Health Aging
.
2015
Oct
;
19
(
8
):
812
8
.
[PubMed]
1279-7707
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