Flowchart: Preparation: Fto
 

 


                  

Text Box: AlkB Text Box: Fto                                                     

                                                                               

                          

Obesity

Diabetes  

Text Box: Rbl2                                                        

 

 

 

2010/5/11

 

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A commonly carried allele of the obesity-related FTO gene is associated with reduced brain volume in the healthy elderly.

Ho AJ, Stein JL, Hua X, Lee S, Hibar DP, Leow AD, Dinov ID, Toga AW, Saykin AJ, Shen L, Foroud T, Pankratz N, Huentelman MJ, Craig DW, Gerber JD, Allen AN, Corneveaux JJ, Stephan DA, Decarli CS, Dechairo BM, Potkin SG, Jack CR Jr, Weiner MW, Raji CA, Lopez OL, Becker JT, Carmichael OT, Thompson PM; the Alzheimer's Disease Neuroimaging Initiative.

Laboratory of Neuroimaging, Department of Neurology, University of California School of Medicine, Los Angeles, CA 90095.

Abstract

A recently identified variant within the fat mass and obesity-associated (FTO) gene is carried by 46% of Western Europeans and is associated with an ~1.2 kg higher weight, on average, in adults and an ~1 cm greater waist circumference. With >1 billion overweight and 300 million obese persons worldwide, it is crucial to understand the implications of carrying this very common allele for the health of our aging population. FTO is highly expressed in the brain and elevated body mass index (BMI) is associated with brain atrophy, but it is unknown how the obesity-associated risk allele affects human brain structure. We therefore generated 3D maps of regional brain volume differences in 206 healthy elderly subjects scanned with MRI and genotyped as part of the Alzheimer's Disease Neuroimaging Initiative. We found a pattern of systematic brain volume deficits in carriers of the obesity-associated risk allele versus noncarriers. Relative to structure volumes in the mean template, FTO risk allele carriers versus noncarriers had an average brain volume difference of ~8% in the frontal lobes and 12% in the occipital lobes-these regions also showed significant volume deficits in subjects with higher BMI. These brain differences were not attributable to differences in cholesterol levels, hypertension, or the volume of white matter hyperintensities; which were not detectably higher in FTO risk allele carriers versus noncarriers. These brain maps reveal that a commonly carried susceptibility allele for obesity is associated with structural brain atrophy, with implications for the health of the elderly.

PMID: 20404173 [PubMed - as supplied by publisher]Free Article

Diabetes. 2010 Apr 14. [Epub ahead of print]

Comment on: Jowett et al. (2009) Genetic variation at the FTO locus influences RBL2 gene expression. Diabetes, published online December 15, 2009.

Berulava T, Horsthemke B.

Institut für Humangenetik, Universitätsklinikum Essen, Germany.

PMID: 20393146 [

-         PMID:20152788 [PubMed - indexed for MEDLINE]

 

Nature.2010 Apr 22;464(7292):1205-9. Epub 2010 Apr 7.

Crystal structure of theFTO protein reveals basis for its substrate specificity.

Han Z,Niu T,Chang J,Lei X,Zhao M,Wang Q,Cheng W,Wang J,Feng Y,Chai J.

National Institute ofBiological Sciences, No. 7 Science Park Road, Beijing 102206, China.

Abstract

Recent studies haveunequivocally associated the fat mass and obesity-associated (FTO) genewith the risk of obesity. In vitro FTO protein is an AlkB-like DNA/RNAdemethylase with a strong preference for 3-methylthymidine (3-meT) insingle-stranded DNA or 3-methyluracil (3-meU) in single-stranded RNA. Herewe report the crystal structure of FTO in complex with the mononucleotide3-meT. FTO comprises an amino-terminal AlkB-like domain and acarboxy-terminal domain with a novel fold. Biochemical assays show thatthese two domains interact with each other, which is required for FTOcatalytic activity. In contrast with the structures of other AlkB members,FTO possesses an extra loop covering one side of the conserved jelly-rollmotif. Structural comparison shows that this loop selectively competes withthe unmethylated strand of the DNA duplex for binding to FTO, suggestingthat it has an important role in FTO selection against double-strandednucleic acids. The ability of FTO to distinguish 3-meT or 3-meU from othernucleotides is conferred by its hydrogen-bonding interaction with the twocarbonyl oxygen atoms in 3-meT or 3-meU. Taken together, these resultsprovide a structural basis for understanding FTO substrate-specificity, andserve as a foundation for the rational design of FTO inhibitors.

PMID:20376003 [PubMed -