Web of Science: 128 cites, Scopus: 144 cites, Google Scholar: cites
Hypothalamic-specific manipulation of Fto , the ortholog of the human obesity gene FTO , affects food intake in rats
Tung, Yi-Chun Loraine (University of Cambridge. Metabolic Research Laboratories)
Ayuso, Eduard (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
Shan, Xiaoye (University of Cambridge. Metabolic Research Laboratories)
Bosch i Tubert, Fàtima (Universitat Autònoma de Barcelona. Departament de Bioquímica i de Biologia Molecular)
O'Rahilly, Stephen (University of Cambridge. Metabolic Research Laboratories)
Coll, Anthony P. (University of Cambridge. Metabolic Research Laboratories)
Yeo, Gilles S. H. (University of Cambridge. Metabolic Research Laboratories)

Data: 2010
Resum: Sequence variants in the first intron of FTO are strongly associated with human obesity and human carriers of the risk alleles show evidence for increased appetite and food intake. Mice globally lacking Fto display a complex phenotype characterised by both increased energy expenditure and increased food intake. The site of action of FTO on energy balance is unclear. Fasting reduces levels of Fto mRNA in the arcuate nucleus (ARC) of the hypothalamus, a site where Fto expression is particularly high. In this study, we have extended this nutritional link by demonstrating that consumption of a high fat diet (45%) results in a 2. 5 fold increase in Arc Fto expression. We have further explored the role of hypothalamic Fto in the control of food intake by using stereotactic injections coupled with AAV technology to bi-directionally modulate Fto expression. An over expression of Fto protein by 2. 5-fold in the ARC results in a 14% decrease in average daily food intake in the first week. In contrast, knocking down Arc Fto expression by 40% increases food intake by 16%. mRNA levels of Agrp, Pomc and Npy, ARC-expressed genes classically associated with the control of food intake, were not affected by the manipulation of Fto expression. However, over expression of Fto resulted in a 4-fold increase in the mRNA levels of Stat3, a signalling molecule critical for leptin receptor signalling, suggesting a possible candidate for the mediation of Fto's actions. These data provide further support for the notion that FTO itself can influence key components of energy balance, and is therefore a strong candidate for the mediation of the robust association between FTO intronic variants and adiposity. Importantly, this provide the first indication that selective alteration of FTO levels in the hypothalamus can influence food intake, a finding consistent with the reported effects of FTO alleles on appetite and food intake in man.
Ajuts: European Commission 512013
European Commission 241592
Ministerio de Ciencia e Innovación SAF2008-00962
Nota: Altres ajuts: CLINIGENE/LSHB-CT-2006-018933
Nota: Altres ajuts: UK/MRC-CORD
Drets: Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. Creative Commons
Llengua: Anglès
Document: Article ; Versió publicada
Matèria: Obesitat ; Obesity ; Fto
Publicat a: PloS one, Vol. 5, Issue 1 (January 2010) , p. e8771, ISSN 1932-6203

DOI: 10.1371/journal.pone.0008771
PMID: 20098739

8 p, 490.0 KB

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