FTO genotype and aging: pleiotropic longitudinal effects on adiposity, brain function, impulsivity and diet

Abstract

Although overweight and obesity are associated with poor health outcomes in the elderly, the biological bases of obesity-related behaviors during aging are poorly understood. Common variants in the FTO gene are associated with adiposity in children and younger adults as well as with adverse mental health in older individuals. However, it is unclear whether FTO influences longitudinal trajectories of adiposity and other intermediate phenotypes relevant to mental health during aging. We examined whether a commonly carried obesity-risk variant in the FTO gene (rs1421085 single-nucleotide polymorphism) influences adiposity and is associated with changes in brain function in participants within the Baltimore Longitudinal Study of Aging, one of the longest-running longitudinal aging studies in the United States. Our results show that obesity-related risk allele carriers of FTO gene show dose-dependent increments in body mass index during aging. Moreover, the obesity-related risk allele is associated with reduced medial prefrontal cortical function during aging. Consistent with reduced brain function in regions intrinsic to impulse control and taste responsiveness, risk allele carriers of FTO exhibit dose-dependent increments in both impulsivity and intake of fatty foods. We propose that a common neural mechanism may underlie obesity-associated impulsivity and increased consumption of high-calorie foods during aging.

Figure 1

Schematic representation of the study design and work flow A) Our first aim was to test whether FTO genotype (rs1421085 single nucleotide polymorphism; obesity-risk allele-C) influenced trajectories of adiposity during aging in the BLSA B) The second aim was to examine the association between FTO genotype and longitudinal changes in brain function, measured by serial resting state cerebral blood flow (rCBF) through ¹⁵O-water PET imaging in the neuroimaging substudy of the BLSA (BLSA-NI) C) Finally, based on our longitudinal rCBF results implicating brain regions involved in impulse control and taste responsiveness to food, we tested whether FTO genotype influenced longitudinal changes in impulsivity and macronutrient intake patterns during aging. Abbreviations: BLSA, Baltimore Longitudinal Study of Aging; FTO, fat mass and obesity associated gene

Figure 2

The effect of FTO genotype (rs1421085 single nucleotide polymorphism; obesity-risk allele-C) on age- and sex-adjusted trajectories of body mass index (BMI) during aging. Trajectories of BMI over time were significantly different between obesity risk allele non-carriers, heterozygous and homozygous individuals (likelihood ratio test: χ²=13.7, df=4, p=0.008)

Figure 3

Differences in longitudinal changes in regional resting state cerebral blood flow (rCBF) between obesity risk allele carriers (FTO+) and non-carriers (FTO−). Blue areas indicate brain regions that show significantly greater longitudinal decreases in rCBF in the FTO+ group; red areas indicate brain regions that show greater longitudinal increases in rCBF in the FTO+ group. (A) axial view (B) sagittal view.

Figure 4

The effect of FTO genotype (rs1421085 single nucleotide polymorphism; obesity-risk allele-C) on trajectories of excitement-seeking (A) and fat intake (B) during aging from the mixed-effects models. The trajectories were presented at 3 different baseline age periods: 50–60, 60–70, 70–80 years of age. A. In general, excitement-seeking decreased as age increased. The presence of obesity risk alleles was associated with less decrease in excitement-seeking over time in all age periods. B. Similarly, fat intake decreased during aging. In general, the presence of obesity risk alleles was associated with less decrease in fat intake over time and at later age periods, 70–80 years of age, homozygous risk alleles carriers even showed increase in fat intake over time.