Fat mass-and obesity-associated (FTO) gene variant is associated with obesity: longitudinal analyses in two cohort studies and functional test.
OBJECTIVE
To examine the longitudinal association of fat mass-and obesity-associated (FTO) variant with obesity, circulating adipokine levels, and FTO expression in various materials from human and mouse.


METHODS
We genotyped rs9939609 in 2,287 men and 3,520 women from two prospective cohorts. Plasma adiponectin and leptin were measured in a subset of diabetic men (n = 854) and women (n = 987). Expression of FTO was tested in adipocytes from db/db mice and mouse macrophages.


RESULTS
We observed a trend toward decreasing associations between rs9939609 and BMI at older age (>or=65 years) in men, whereas the associations were constant across different age groups in women. In addition, the single nucleotide polymorphism (SNP) rs9939609 was associated with lower plasma adiponectin (log[e]--means, 1.82 +/- 0.04, 1.73 +/- 0.03, and 1.68 +/- 0.05 for TT, TA, and AA genotypes, respectively; P for trend = 0.02) and leptin (log[e]--means, 3.56 +/- 0.04, 3.63 +/- 0.04, and 3.70 +/- 0.06; P for trend = 0.06) in diabetic women. Adjustment for BMI attenuated the associations. FTO gene was universally expressed in human and mice tissues, including adipocytes. In an ancillary study of adipocytes from db/db mice, FTO expression was approximately 50% lower than in those from wild-type mice.


CONCLUSIONS
The association between FTO SNP rs9939609 and obesity risk may decline at older age. The variant affects circulating adiponectin and leptin levels through the changes in BMI. In addition, the expression of FTO gene was reduced in adipocytes from db/db mice.
Qi
Lu
L
Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA. nhlqi@channing.harvard.edu
Kang
Kihwa
K
Zhang
Cuilin
C
van Dam
Rob M
RM
Kraft
Peter
P
Hunter
David
D
Lee
Chih-Hao
CH
Hu
Frank B
FB
D017667:Adipocytes / Q000166:cytology / Q000378:metabolism; D054392:Adipokines / Q000097:blood; D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; D000818:Animals; D015992:Body Mass Index; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000235:genetics / Q000378:metabolism; D005223:Fats / Q000378:metabolism*; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006801:Humans; D008137:Longitudinal Studies; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D006899:Mixed Function Oxygenases; D009206:Myocardium / Q000378:metabolism; D009765:Obesity / Q000097:blood / Q000235:genetics* / Q000378:metabolism; D007652:Oxo-Acid-Lyases / Q000235:genetics*; D011506:Proteins / Q000235:genetics*
D054392:Adipokines; D005223:Fats; D011506:Proteins; D006899:Mixed Function Oxygenases; C524916:FTO protein, mouse; D000071516:Alpha-Ketoglutarate-Dependent Dioxygenase FTO; C526492:FTO protein, human; D007652:Oxo-Acid-Lyases