FTO Genotype and 2-Year Change in Body Composition and Fat Distribution in Response to Weight-Loss Diets


Xiaomin Zhang; Qibin Qi; Cuilin Zhang; Frank B. Hu; Frank M. Sacks; Lu Qi


Diabetes. 2012;61(11):3005-3011. 

In This Article

Abstract and Introduction


Recent evidence suggests that the fat mass and obesity-associated gene (FTO) genotype may interact with dietary intakes in relation to adiposity. We tested the effect of FTO variant on weight loss in response to 2-year diet interventions. FTO rs1558902 was genotyped in 742 obese adults who were randomly assigned to one of four diets differing in the proportions of fat, protein, and carbohydrate. Body composition and fat distribution were measured by dual-energy x-ray absorptiometry and computed tomography. We found significant modification effects for intervention varying in dietary protein on 2-year changes in fat-free mass, whole body total percentage of fat mass, total adipose tissue mass, visceral adipose tissue mass, and superficial adipose tissue mass (for all interactions, P < 0.05). Carriers of the risk allele had a greater reduction in weight, body composition, and fat distribution in response to a high-protein diet, whereas an opposite genetic effect was observed on changes in fat distribution in response to a low-protein diet. Likewise, significant interaction patterns also were observed at 6 months. Our data suggest that a high-protein diet may be beneficial for weight loss and improvement of body composition and fat distribution in individuals with the risk allele of the FTO variant rs1558902.


The prevalence of overweight and obesity has increased substantially in the U.S. and worldwide, and the health burden of obesity-related complications has grown accordingly.[1–3] Obesity is primarily determined by both genetic and lifestyle factors, including diet, as well as their interactions.[4] In the past few years, genome-wide association studies (GWASs) have identified a group of genetic loci associated with BMI and obesity risk.[5–7] Among them, the fat mass and obesity-associated gene (FTO) locus shows the strongest effect.[5,8] Accumulating evidence has suggested that this locus is involved in the hypothalamic regulation of appetite and dietary energy intake.[9,10]

Recently, several studies have examined the effect of the FTO-diet interaction on body weight, but the results are not entirely consistent. Several cross-sectional studies showed that dietary factors such as low fat intake might modify the genetic effect of FTO on BMI or fat distribution.[11–13] However, the gene by diet interaction was not univocally observed in randomized intervention trials,[13–17] although one study found that a Mediterranean diet intervention modified the association between the FTO variant and weight changes in a population with high cardiovascular risk.[18] These intervention trials, however, largely are limited by relatively small sample size or the short term of follow-up. In addition, animal studies have suggested that FTO might differentially affect various body compositions and fat distribution at different depots.[19–21] Few studies have evaluated systematically the effect of the FTO variant on these measurements.

The POUNDS LOST Trial thus far is the largest 2-year randomized intervention trial that tested the effect of four diets varying in proportions of fat, protein, and carbohydrate on weight loss in overweight or obese subjects.[22] By use of the data from this trial, we evaluated whether various weight-loss diets might modify the effect of the FTO variant on weight loss and long-term changes in body composition and fat distribution.