Association between the FTO rs9939609 single nucleotide polymorphism and dietary adherence during a 2-year caloric restriction intervention: exploratory analyses from CALERIE phase 2

Authors: DORLING, JAMES - University Of Glasgow; BELSKY, DANIEL - Columbia University - New York; RACETTE, SUSAN - Washington University; DAS, SAI KRUPA - Jean Mayer Human Nutrition Research Center On Aging At Tufts University; RAVUSSIN, ERIC - Pennington Biomedical Research Center; REDMAN, LEANNE - Pennington Biomedical Research Center; HOCHSMANN, CHRISTOPHER - Pennington Biomedical Research Center; HUFFMAN, KIM - Duke University; KRAUS, WILLIAM - Duke University; KOBOR, MICHAEL - University Of British Columbia; MACISAAC, JULIA - University Of British Columbia; LIN, DAVID - University Of British Columbia; CORCORAN, DAVID - Duke University; MARTIN, CORBY - Pennington Biomedical Research Center

Submitted to: Experimental Gerontology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 9/9/2021
Publication Date: 9/21/2021
Citation: Dorling, J.L., Belsky, D.W., Racette, S.B., Das, S., Ravussin, E., Redman, L.M., Hochsmann, C., Huffman, K.M., Kraus, W.E., Kobor, M.S., Macisaac, J.L., Lin, D.T., Corcoran, D.L., Martin, C.K. 2021. Association between the FTO rs9939609 single nucleotide polymorphism and dietary adherence during a 2-year caloric restriction intervention: exploratory analyses from CALERIE phase 2. Experimental Gerontology. https://doi.org/10.1016/j.exger.2021.111555.
DOI: https://doi.org/10.1016/j.exger.2021.111555

Interpretive Summary: Previous research suggests that calorie restriction may improve indicators of aging in humans. However, it is unknown whether differences in genetic makeup alter the ability to stick to calorie restriction or experience its benefits. Individuals with a specific variant in the FTO gene (a gene associated with body fat and obesity) tend to have greater appetite and higher weight than individuals without the variant. This analysis aimed to determine whether individuals with the FTO variant demonstrated differences in their ability to follow calorie restriction, body fat, metabolism, diet-related hormones, or eating behavior during the Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE) 2 study. Results showed that individuals with the FTO gene variant did not differ from those without the variant on most measures that were studied. These findings suggest that calorie restriction programs may be beneficial to populations without obesity and do not need to be altered for individuals who have the FTO gene variant.

Technical Abstract: Caloric restriction (CR) improves markers of aging in humans; but it is not known if the fat mass and obesity-associated gene (FTO) rs9939609 single nucleotide polymorphism (SNP), which is associated with appetite and energy intake, influences adherence to prolonged CR. Utilizing data from the two-year Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) phase 2 randomized controlled trial, we tested whether the FTO rs9939609 SNP was associated with adherence to CR in healthy adults without obesity. As secondary aims, we assessed whether the FTO rs9939609 SNP was associated with changes in body composition, biomarkers of aging, and eating behaviors. Participants were randomized into either a CR group that targeted a 25% reduction in energy intake compared to the habitual energy intake at baseline, or an ad libitum (AL) control group. Participants were genotyped for the FTO rs9939609 SNP. Dietary adherence was determined through changes in energy intake using doubly labeled water and changes in body composition at baseline, month 12, and month 24 in both the CR and AL condition. Weight, body composition, resting metabolic rate (RMR), adiponectin, insulin, leptin, and eating behaviors were measured at the same timepoints. A total of 144 participants (91 CR and 53 AL, age: 38.6 +/- 7.1 years; body mass index: 25.3 +/- 1.7 kg/m2) were studied. Of these, 27 were homozygous for the 'obesity-risk' A allele (AA), while 44 were homozygous for the T allele (TT) and 73 were heterozygotes (AT). By design, the CR group exhibited greater percent CR compared to the AL group during the trial (P < 0.01), but no genotype-by-treatment interaction was observed for change in energy intake or percent CR (P >= 0.40). The FTO rs9939609 SNP was also negligibly associated with change in most other endpoints (P >= 0.13), though AAs showed a reduction in RMR adjusted for body composition change over the 24 months relative to TTs (genotype-by-treatment interaction: P = 0.03). In a two-year CR intervention delivered to healthy individuals without obesity, the FTO rs9939609 SNP was not associated with adherence to CR and did not alter improvements in most aging biomarkers.