Macronutrient-specific effect of FTO rs9939609 in response to a 10-week randomized hypo-energetic diet among obese Europeans

Background: The A risk allele of rs9939609 of the fat mass- and obesity-associated gene (FTO) increases body fat mass. Objective: To examine whether FTO rs9939609 affects obese individuals' response to a high-fat, low-carbohydrate (CHO) (HF) or low-fat, high-CHO (LF), hypo-energetic diet and whether the effect of the FTO variant depends on dietary fat and CHO content. Design: In a 10-week, European, multi-centre dietary intervention study 771 obese women and men were randomized to either LF (20-25% of energy (%E) from fat, 60-65% E from CHO) or HF (40-45% E from fat, 40-45% E from CHO), hypo-energetic diet (measured resting metabolic rate multiplied by 1.3-600 kcal day(-1)). Body weight, fat mass (FM), fat-free mass (FFM), waist circumference (WC), resting energy expenditure (REE), fasting fat oxidation as % of REE (FatOx), insulin release (HOMA-beta) and a surrogate measure of insulin resistance (HOMA-IR) were measured at baseline and after the intervention. In all, 764 individuals were genotyped for FTO rs9939609. Results: For A-allele carriers the drop-out rate was higher on HF than LF diet (in AT, P = 0.002; in AT/AA combined, P = 0.003). Among those individuals completing the intervention, we found no effect of FTO rs9939609 genotype on Delta weight, Delta FM, Delta FFM, Delta WC or Delta FatOx. However, participants with TT had a smaller reduction in REE on LF than on HF diet (75 kcal/24 h; interaction: P = 0.0055). These individuals also showed the greatest reduction in HOMA-beta and HOMA-IR (interaction: P = 0.0083 and P = 0.047). Conclusion: The FTO rs9939609 may interact with the macronutrient composition in weight loss diets in various ways; carriers of the A allele on LF diet appear to have a lower risk for drop out, and TT individuals have a smaller decrease in REE and greater decrease in HOMA-beta and HOMA-IR on LF than on HF diet. International Journal of Obesity (2009) 33, 1227-1234; doi:10.1038/ijo.2009.159; published online 18 August 2009