PMID- 29459251
OWN - NLM
STAT- MEDLINE
DCOM- 20190315
LR  - 20190315
IS  - 2212-8778 (Electronic)
IS  - 2212-8778 (Linking)
VI  - 10
DP  - 2018 Apr
TI  - Prolyl carboxypeptidase in Agouti-related Peptide neurons modulates food intake 
      and body weight.
PG  - 28-38
LID - S2212-8778(18)30004-8 [pii]
LID - 10.1016/j.molmet.2018.02.003 [doi]
AB  - OBJECTIVE: Prolyl carboxypeptidase (PRCP) plays a role in the regulation of 
      energy metabolism by inactivating hypothalamic alpha-melanocyte stimulating hormone 
      (alpha-MSH) levels. Although detected in the arcuate nucleus, limited PRCP expression 
      has been observed in the arcuate POMC neurons, and its site of action in 
      regulating metabolism is still ill-defined. METHODS: We performed immunostaining 
      to assess the localization of PRCP in arcuate Neuropeptide Y/Agouti-related 
      Peptide (NPY/AgRP) neurons. Hypothalamic explants were then used to assess the 
      intracellular localization of PRCP and its release at the synaptic levels. 
      Finally, we generated a mouse model to assess the role of PRCP in NPY/AgRP 
      neurons of the arcuate nucleus in the regulation of metabolism. RESULTS: Here we 
      show that PRCP is expressed in NPY/AgRP-expressing neurons of the arcuate 
      nucleus. In hypothalamic explants, stimulation by ghrelin increased PRCP 
      concentration in the medium and decreased PRCP content in synaptic extract, 
      suggesting that PRCP is released at the synaptic level. In support of this, 
      hypothalamic explants from mice with selective deletion of PRCP in AgRP neurons 
      (Prcp(AgRPKO)) showed reduced ghrelin-induced PRCP concentration in the medium 
      compared to controls mice. Furthermore, male Prcp(AgRPKO) mice had decreased body 
      weight and fat mass compared to controls. However, this phenotype was 
      sex-specific as female Prcp(AgRPKO) mice show metabolic differences only when 
      challenged by high fat diet feeding. The improved metabolism of Prcp(AgRPKO) mice 
      was associated with reduced food intake and increased energy expenditure, 
      locomotor activity, and hypothalamic alpha-MSH levels. Administration of SHU9119, a 
      potent melanocortin receptor antagonist, selectively in the PVN of Prcp(AgRPKO) 
      male mice increased food intake to a level similar to that of control mice. 
      CONCLUSIONS: Altogether, our data indicate that PRCP is released at the synaptic 
      levels and that PRCP in AgRP neurons contributes to the modulation of alpha-MSH 
      degradation and related metabolic control in mice.
CI  - Copyright (c) 2018 The Authors. Published by Elsevier GmbH.. All rights reserved.
FAU - Bruschetta, Giuseppe
AU  - Bruschetta G
AD  - Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale 
      University School of Medicine, New Haven, CT, 06520, USA; Department of 
      Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of 
      Medicine, New Haven, CT, 06520, USA.
FAU - Jin, Sungho
AU  - Jin S
AD  - Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale 
      University School of Medicine, New Haven, CT, 06520, USA; Department of 
      Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of 
      Medicine, New Haven, CT, 06520, USA.
FAU - Kim, Jung Dae
AU  - Kim JD
AD  - Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale 
      University School of Medicine, New Haven, CT, 06520, USA; Department of 
      Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of 
      Medicine, New Haven, CT, 06520, USA.
FAU - Diano, Sabrina
AU  - Diano S
AD  - Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale 
      University School of Medicine, New Haven, CT, 06520, USA; Department of 
      Obstetrics, Gynecology, and Reproductive Sciences, Yale University School of 
      Medicine, New Haven, CT, 06520, USA; Department of Neuroscience, Yale University 
      School of Medicine, New Haven, CT, 06520, USA; Department of Comparative 
      Medicine, Yale University School of Medicine, New Haven, CT, 06520, USA. 
      Electronic address: sabrina.diano@yale.edu.
LA  - eng
GR  - R01 DK097566/DK/NIDDK NIH HHS/United States
GR  - R01 DK105571/DK/NIDDK NIH HHS/United States
GR  - R01 DK107293/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20180208
PL  - Germany
TA  - Mol Metab
JT  - Molecular metabolism
JID - 101605730
RN  - 0 (Agouti-Related Protein)
RN  - 0 (Peptide Fragments)
RN  - 0 (agouti-related peptide, (Yc(CRFFNAFC)Y))
RN  - 581-05-5 (alpha-MSH)
RN  - EC 3.4.- (Carboxypeptidases)
RN  - EC 3.4.16.2 (lysosomal Pro-X carboxypeptidase)
SB  - IM
MH  - Agouti-Related Protein/genetics/metabolism
MH  - Animals
MH  - Arcuate Nucleus of Hypothalamus/cytology/metabolism
MH  - *Body Weight
MH  - Carboxypeptidases/genetics/*metabolism
MH  - *Eating
MH  - Male
MH  - Mice
MH  - Neurons/*metabolism
MH  - Peptide Fragments/genetics/metabolism
MH  - Synapses/metabolism
MH  - alpha-MSH/metabolism
PMC - PMC5985234
OTO - NOTNLM
OT  - Energy metabolism
OT  - Food intake
OT  - NPY/AgRP
OT  - Prolyl carboxypeptidase
OT  - alpha-MSH
EDAT- 2018/02/21 06:00
MHDA- 2019/03/16 06:00
PMCR- 2018/02/08
CRDT- 2018/02/21 06:00
PHST- 2018/01/02 00:00 [received]
PHST- 2018/01/26 00:00 [revised]
PHST- 2018/02/04 00:00 [accepted]
PHST- 2018/02/21 06:00 [pubmed]
PHST- 2019/03/16 06:00 [medline]
PHST- 2018/02/21 06:00 [entrez]
PHST- 2018/02/08 00:00 [pmc-release]
AID - S2212-8778(18)30004-8 [pii]
AID - 10.1016/j.molmet.2018.02.003 [doi]
PST - ppublish
SO  - Mol Metab. 2018 Apr;10:28-38. doi: 10.1016/j.molmet.2018.02.003. Epub 2018 Feb 8.