Document Detail

Ghrelin effects on neuropeptides in the rat hypothalamus depend on fatty acid metabolism actions on BSX but not on gender.
MedLine Citation:
PMID:  20335227     Owner:  NLM     Status:  MEDLINE    
The orexigenic effect of ghrelin is mediated by neuropeptide Y (NPY) and agouti-related protein (AgRP) in the hypothalamic arcuate nucleus (ARC). Recent evidence also indicates that ghrelin promotes feeding through a mechanism involving activation of hypothalamic AMP-activated protein kinase (AMPK) and inactivation of acetyl-CoA carboxylase and fatty acid synthase (FAS). This results in decreased hypothalamic levels of malonyl-CoA, increased carnitine palmitoyltransferase 1 (CPT1) activity, and mitochondrial production of reactive oxygen species. We evaluated whether these molecular events are part of a unique signaling cascade or whether they represent alternative pathways mediating the orexigenic effect of ghrelin. Moreover, we examined the gender dependency of these mechanisms, because recent evidence has proposed that ghrelin orexigenic effect is reduced in female rats. We studied in both genders the effect of ghrelin on the expression of AgRP and NPY, as well as their transcription factors: cAMP response-element binding protein (CREB and its phosphorylated form, pCREB), forkhead box O1 (FoxO1 and its phosphorylated form, pFoxO1), and brain-specific homeobox transcription factor (BSX). In addition, to establish a mechanistic link between ghrelin, fatty acid metabolism, and neuropeptides, we evaluated the effect of ghrelin after blockage of hypothalamic fatty acid beta oxidation, by using the CPT1 inhibitor etomoxir. Ghrelin-induced changes in the AMPK-CPT1 pathway are associated with increased levels of AgRP and NPY mRNA expression through modulation of BSX, pCREB, and FoxO1, as well as decreased expression of endoplasmic reticulum (ER) stress markers in a gender-independent manner. In addition, blockage of hypothalamic fatty acid beta oxidation prevents the ghrelin-promoting action on AgRP and NPY mRNA expression, also in a gender-independent manner. Notably, this effect is associated with decreased BSX expression and reduced food intake. Overall, our data suggest that BSX integrates changes in neuronal metabolic status with ARC-derived neuropeptides in a gender-independent manner.
Ricardo Lage; María J Vázquez; Luis Varela; Asish K Saha; Antonio Vidal-Puig; Rubén Nogueiras; Carlos Diéguez; Miguel López
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2010-03-24
Journal Detail:
Title:  FASEB journal : official publication of the Federation of American Societies for Experimental Biology     Volume:  24     ISSN:  1530-6860     ISO Abbreviation:  FASEB J.     Publication Date:  2010 Aug 
Date Detail:
Created Date:  2010-08-03     Completed Date:  2010-09-07     Revised Date:  2014-02-19    
Medline Journal Info:
Nlm Unique ID:  8804484     Medline TA:  FASEB J     Country:  United States    
Other Details:
Languages:  eng     Pagination:  2670-9     Citation Subset:  IM    
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MeSH Terms
Agouti-Related Protein / drug effects,  genetics
Fatty Acids / metabolism*
Gene Expression Regulation
Ghrelin / pharmacology*
Homeodomain Proteins / genetics*
Hypothalamus / metabolism*
Nerve Tissue Proteins / metabolism*
Neuropeptide Y / drug effects,  genetics
Neuropeptides / drug effects*,  genetics
Sex Factors
Transcription Factors / genetics,  metabolism*
Grant Support
DK-67509/DK/NIDDK NIH HHS; G0600717//Medical Research Council; G0802051//Medical Research Council; K-19514//PHS HHS; //Medical Research Council; //Wellcome Trust
Reg. No./Substance:
0/Agouti-Related Protein; 0/BSX protein, rat; 0/Fatty Acids; 0/Ghrelin; 0/Homeodomain Proteins; 0/Nerve Tissue Proteins; 0/Neuropeptide Y; 0/Neuropeptides; 0/Transcription Factors

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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