PMID- 23493572
OWN - NLM
STAT- MEDLINE
DCOM- 20130909
LR  - 20211021
IS  - 1939-327X (Electronic)
IS  - 0012-1797 (Print)
IS  - 0012-1797 (Linking)
VI  - 62
IP  - 7
DP  - 2013 Jul
TI  - Hypothalamic ceramide levels regulated by CPT1C mediate the orexigenic effect of 
      ghrelin.
PG  - 2329-37
LID - 10.2337/db12-1451 [doi]
AB  - Recent data suggest that ghrelin exerts its orexigenic action through regulation 
      of hypothalamic AMP-activated protein kinase pathway, leading to a decline in 
      malonyl-CoA levels and desinhibition of carnitine palmitoyltransferase 1A 
      (CPT1A), which increases mitochondrial fatty acid oxidation and ultimately 
      enhances the expression of the orexigenic neuropeptides agouti-related protein 
      (AgRP) and neuropeptide Y (NPY). However, it is unclear whether the 
      brain-specific isoform CPT1C, which is located in the endoplasmic reticulum of 
      neurons, may play a role in this action. Here, we demonstrate that the orexigenic 
      action of ghrelin is totally blunted in CPT1C knockout (KO) mice, despite having 
      the canonical ghrelin signaling pathway activated. We also demonstrate that 
      ghrelin elicits a marked upregulation of hypothalamic C18:0 ceramide levels 
      mediated by CPT1C. Notably, central inhibition of ceramide synthesis with 
      myriocin negated the orexigenic action of ghrelin and normalized the levels of 
      AgRP and NPY, as well as their key transcription factors phosphorylated 
      cAMP-response element-binding protein and forkhead box O1. Finally, central 
      treatment with ceramide induced food intake and orexigenic neuropeptides 
      expression in CPT1C KO mice. Overall, these data indicate that, in addition to 
      formerly reported mechanisms, ghrelin also induces food intake through regulation 
      of hypothalamic CPT1C and ceramide metabolism, a finding of potential importance 
      for the understanding and treatment of obesity.
FAU - Ramirez, Sara
AU  - Ramirez S
AD  - Basic Sciences Department, Faculty of Medicine and Health Sciences, Universitat 
      Internacional de Catalunya, Barcelona, Spain.
FAU - Martins, Luis
AU  - Martins L
FAU - Jacas, Jordi
AU  - Jacas J
FAU - Carrasco, Patricia
AU  - Carrasco P
FAU - Pozo, Macarena
AU  - Pozo M
FAU - Clotet, Josep
AU  - Clotet J
FAU - Serra, Dolors
AU  - Serra D
FAU - Hegardt, Fausto G
AU  - Hegardt FG
FAU - Dieguez, Carlos
AU  - Dieguez C
FAU - Lopez, Miguel
AU  - Lopez M
FAU - Casals, Nuria
AU  - Casals N
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130314
PL  - United States
TA  - Diabetes
JT  - Diabetes
JID - 0372763
RN  - 0 (Agouti-Related Protein)
RN  - 0 (Ceramides)
RN  - 0 (Ghrelin)
RN  - 0 (Neuropeptide Y)
RN  - EC 2.3.1.21 (Carnitine O-Palmitoyltransferase)
SB  - IM
MH  - Agouti-Related Protein/genetics/metabolism
MH  - Animals
MH  - Carnitine O-Palmitoyltransferase/genetics/*metabolism
MH  - Ceramides/*metabolism
MH  - Eating/drug effects/*physiology
MH  - Ghrelin/*pharmacology
MH  - Hypothalamus/drug effects/*metabolism
MH  - Male
MH  - Mice
MH  - Mice, Knockout
MH  - Neuropeptide Y/genetics/metabolism
MH  - Signal Transduction/drug effects/physiology
PMC - PMC3712075
EDAT- 2013/03/16 06:00
MHDA- 2013/09/10 06:00
PMCR- 2014/07/01
CRDT- 2013/03/16 06:00
PHST- 2013/03/16 06:00 [entrez]
PHST- 2013/03/16 06:00 [pubmed]
PHST- 2013/09/10 06:00 [medline]
PHST- 2014/07/01 00:00 [pmc-release]
AID - db12-1451 [pii]
AID - 1451 [pii]
AID - 10.2337/db12-1451 [doi]
PST - ppublish
SO  - Diabetes. 2013 Jul;62(7):2329-37. doi: 10.2337/db12-1451. Epub 2013 Mar 14.