Dietary Fat Modifies the Effects of FTO Genotype on Changes in Insulin Sensitivity

Abstract

Background: The common variants in the fat mass and obesity-associated (FTO) gene have been associated with obesity and insulin resistance. Recently, studies also linked FTO variants with macronutrient intakes.

Objective: We aimed to investigate whether diet interventions varying in macronutrients modified the effects of FTO genotypes on changes in insulin resistance.

Methods: We genotyped FTO variants rs1558902 and rs9939609 and measured insulin resistance in fasting plasma samples at baseline and at 6-mo and 2-y visits in 743 overweight or obese adults (aged 30-70 y, 60% women) from a randomized weight-loss dietary interventional trial, the Preventing Overweight Using Novel Dietary Strategies (POUNDS LOST) trial. We assessed interactions between FTO variants and intakes of dietary fat and protein in relation to change in body weight and insulin resistance using generalized estimating equation models.

Results: We found significant interactions between rs1558902 and dietary fat on changes in homeostasis model assessment of insulin resistance (HOMA-IR) and insulin (P = 0.003 and 0.004, respectively). Each risk allele (A) of rs1558902 showed a trend to be related to a 0.05-unit less reduction in both log(insulin) and log(HOMA-IR) among the participants assigned to low-fat diets (both P = 0.06), but this was not significantly related to reduction in those assigned to high-fat diets (both P > 0.1) during the 2-y period of intervention. Our data showed that the association between rs9939609 and changes in insulin resistance was not modified by diet macronutrient intakes.

Conclusions: Our results show that carriers of the risk alleles of rs1558902 benefit differently in improving insulin sensitivity by consuming high-fat weight-loss diets rather than low-fat diets. Still, given our data, we acknowledge it is difficult to determine whether fat or carbohydrate contributed to the observed associations.

Trial registration: ClinicalTrials.gov NCT00072995.

Keywords: FTO; diabetes; dietary intervention; gene-diet interaction; insulin resistance.

Conflict of interest statement

Author disclosures: Y Zheng, T Huang, X Zhang, J Rood, GA Bray, FM Sacks, and L Qi, no conflicts of interest.

© 2015 American Society for Nutrition.

Figures

FIGURE 1

Change in insulin resistance measured as HOMA-IR (A) and insulin (B) by FTO rs1558902 genotype and dietary fat groups. P values were adjusted for age, sex, race, weight change, follow-up time, baseline values for respective outcomes, and baseline BMI. Values are means. FTO, fat mass and obesity–associated.

FIGURE 2

Changes from baseline in insulin resistance measured as HOMA-IR (A, B), and insulin (C, D) at the 6-mo and 2-y visits by FTO rs1558902 genotype in both the low-fat and high-fat diet groups. No significant genotype-by-time interactions were detected after adjusting for age, sex, race, weight change, baseline values for respective outcomes, and baseline BMI (all P > 0.05). Values are means. FTO, fat mass and obesity–associated.