Fat Mass–and Obesity-Associated (FTO) Gene Variant Is Associated With Obesity Longitudinal Analyses in Two Cohort Studies and Functional Test

Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA.
Diabetes (Impact Factor: 8.1). 11/2008; 57(11):3145-51. DOI: 10.2337/db08-0006
Source: PubMed


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.
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.
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.
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.

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    • "LPS-induced inflammatory response is mediated through Toll-like receptor (TLR) 4, resulting in the expression of proinflammatory cytokines, such as IL-1β and IL-6. FTO was found to be expressed in leukocytes and was drastically upregulated in mouse macrophages in response to the stimulation of interferon gamma and LPS [14]. Nevertheless, the mechanism underlying the inflammatory stimulants-induced FTO expression is still unknown. "
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    ABSTRACT: The fat mass and obesity associated gene (FTO) is widely investigated in humans regarding its important roles in obesity and type 2 diabetes. Studies in mammals demonstrate that FTO is also associated with inflammation markers. However, the association of FTO with inflammation in chickens remains unclear. In this study, male chickens on day 28 posthatching were injected intraperitoneally with lipopolysaccharide (LPS) or saline to investigate whether the FTO gene is involved in LPS-induced inflammation. We detected significant down-regulation of FTO mRNA in the liver (P < 0.01), but not in the hypothalamus, 2 and 24 h after LPS challenge. Toll-like receptor (TLR) 2 (P < 0.01) and TLR4 (P < 0.01) followed the same pattern as FTO, being suppressed significantly in liver but not in hypothalamus. IL-1beta was dramatically up-regulated (P < 0.01) in both liver and hypothalamus 2 h after LPS challenge, while activation of IL-6 was observed in the liver (P < 0.01), but not in hypothalamus. The 5[prime]-flanking sequence of the chicken FTO gene contains nine predicted binding sites for CCAAT/enhancer binding protein beta (C/EBP beta) and one for signal transducer and activator of transcription 3 (STAT3). Significant elevation of C/EBP beta was detected in the liver (P < 0.01 for fragment 1, P < 0.05 for fragment 2), but not in the hypothalamus, 2 h after LPS challenge. Lipopolysaccharide challenge increased the C/EBP beta binding to FTO promoter in the liver, although the protein content of C/EBP beta was not altered. Moreover, injection of LPS resulted in enhanced phosphorylation of liver STAT3, a downstream transcription factor in IL-6 signaling. Although phosphorylated STAT3 was not detected to directly bind to FTO promoter, it was found to interact with C/EBP beta. Our results reveal that FTO expression in liver, but not in hypothalamus, is affected by the i.p. injection of LPS, which may be mediated through tissue-specific FTO transcriptional regulation by C/EBP beta and STAT3 interaction.
    Full-text · Article · Dec 2013 · BMC Veterinary Research
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    • "Gender association of rs9939609 variant with obesity and BMI in girls is also observed [25]. Association of rs9939609 variant with obesity decreases with age [26]. FTO variant has less effect in old age as compared to young ones [27]. "
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    ABSTRACT: Numerous studies confirmed the association of FTO (fat mass and obesity associated gene) common variant, rs9939609, with obesity in European populations. However, studies in Asian populations revealed conflicting results. We examined the association of rs9939609 variant of FTO gene with obesity and obesity-related anthropometric and metabolic parameters in Pakistani population. Body weight, height, waist circumference, hip circumference, and blood pressure (BP) were measured. BMI and waist-to-hip ratio (WHR) were calculated. Levels of fasting blood glucose (FBG), insulin, leptin, and leptin receptors were measured by enzyme linked immunosorbent assay (ELISA), and homeostasis model assessment of insulin resistance (HOMA-IR) was calculated. The results showed association of FTO gene, rs9939609, with obesity in females (>18 years of age). FTO minor allele increased the risk of obesity by 2.8 times (95% CI = 1.3-6.0) in females. This allele showed association with body weight, BMI, waist circumference, hip circumference, WHR, BP, plasma FBG levels, HOMA-IR, plasma insulin levels, and plasma leptin levels. In conclusion, FTO gene, rs9939609, is associated with BMI and risk of obesity in adult Pakistani females. Association of rs9939609 variant with higher FBG, plasma insulin, and leptin levels indicates that this polymorphism may disturb the metabolism in adult females and predispose them to obesity and type 2 diabetes. However, the above-mentioned findings were not seen in children or males.
    Full-text · Article · Sep 2013
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    • "During adulthood the FTO-associated effect on BMI, or rather on body weight (since changes in BMI during adulthood are due to changes in body mass), remains more or less constant and may even reduce at older age [6] [10] but findings are inconsistent [7]. In addition to the cross-sectional and retrospective studies, the effect of the FTO polymorphism on body weight and its changes has been investigated in a few dietary and exercise interventions [9] [14]. "
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    ABSTRACT: The aim of this study was to investigate whether the polymorphisms of the fat mass and obesity-associated gene (FTO, rs9939609:T>A) and the β2-adrenergic receptor gene (ADRB2, rs1042714:Gln>Glu) are associated with weight loss in dieting obese premenopausal women and the association of these SNPs with body weight, body composition and distribution of fat mass. 75 obese (BMI>30) premenopausal women participated in the intervention including a 3-month weight reduction period and a subsequent 9-month weight maintenance period. Weight and height were measured and BMI calculated. Body composition and fat mass distribution were assessed by dual energy X-ray absorptiometry. At baseline, the AA homozygotes of the FTO gene were 10.1kg heavier (p=0.031), they had higher BMI (p=0.038), and greater waist and greater hip circumference (p=0.08 and p=0.067, respectively) compared to the TT homozygotes. Gln/Gln carriers of the ADRB2 gene had smaller gynoid fat-% compared with both the Gln/Glu and Glu/Glu carriers (p=0.050 and p=0.009, respectively). The Gln homozygotes had also smaller total body fat-% and higher total body lean mass-% than that of the Glu homozygotes (p=0.018 and p=0.019, respectively). FTO genotype was associated with body weight in general, whereas ADRB2 genotype was associated with fat distribution. However, all women in the study group lost weight similarly independently of their genotypes. Neither the FTO nor ADRB2 genotype had statistically significant effect on weight reduction or weight maintenance.
    Full-text · Article · Aug 2013 · Maturitas
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