The rapid rise of obesity during the past decades has coincided with a profound shift of our living environment, including unhealthy dietary patterns, a sedentary lifestyle, and physical inactivity. Genetic predisposition to obesity may have interacted with such an obesogenic environment in determining the obesity epidemic. Growing studies have found that changes in adiposity and metabolic response to low-calorie weight loss diets might be modified by genetic variants related to obesity, metabolic status and preference to nutrients. This review summarized data from recent studies of gene-diet interactions, and discussed integration of research of metabolomics and gut microbiome, as well as potential application of the findings in precision nutrition.

Objective: Alterations in gut microbiota have been linked to host insulin resistance, diabetes and impaired amino acid metabolism. We investigated whether changes in gut microbiota-dependent metabolite of trimethylamine N-oxide (TMAO) and its nutrient precursors (choline and L-carnitine) were associated with improvements in glucose metabolism and diabetes-related amino acids in a weight-loss diet intervention. Design: We included 504 overweight and obese adults who were randomly assigned to one of four energy-reduced diets varying in macronutrient intake. The 6-month changes (Δ) in TMAO, choline and L-carnitine levels after the intervention were calculated. Results: Greater decreases in choline and L-carnitine were significantly (p<0.05) associated with greater improvements in fasting insulin concentrations and homeostasis model assessment of insulin resistance (HOMA-IR) at 6 months. The reduction of choline was significantly related to 2-year improvements in glucose and insulin resistance. We found significant linkages between dietary fat intake and ΔTMAO for changes in fasting glucose, insulin and HOMA-IR (p _interaction <0.05); a greater increase in TMAO was related to lesser improvements in the outcomes among participants who consumed a high-fat diet. In addition, ΔL-carnitine and Δcholine were significantly related to changes in amino acids (including branched-chain and aromatic amino acids). Interestingly, the associations of ΔTMAO, Δcholine and ΔL-carnitine with diabetes-related traits were independent of the changes in amino acids. Conclusion: Our findings underscore the importance of changes in TMAO, choline and L-carnitine in improving insulin sensitivity during a weight-loss intervention for obese patients. Dietary fat intake may modify the associations of TMAO with insulin sensitivity and glucose metabolism. Trial registration number: NCT00072995 .

Plant-based dietary patterns may be related to better cardiovascular profiles. Whether a healthy plant-based dietary index is predictive of future cardiovascular disease (CVD) across people with different genetic susceptibility remains uncertain. We investigated associations of adherence to healthy plant-based diets with the incidence of CVD considering the genetic susceptibility. This prospective cohort study included a total of 156,148 adults initially free of CVD and cancer. We calculated a healthful plant-based diet index (healthful-PDI) in which healthy plant foods received positive scores, and less healthy plant foods and animal foods received reverse scores. Genetic risk scores (GRSs) for myocardial infarction (MI) and stroke were calculated to assess interactions between healthful-PDI and GRSs. During 5 y of follow-up, we observed 1812 incident cases of CVD. Higher healthful-PDI was associated with a lower CVD risk [HR per 10-unit increment: 0.87 (95% CI: 0.81, 0.93) after adjusting for demographic, lifestyle, and other dietary factors (model 1); HR 0.90 (0.84, 0.97) after further adjusting for obesity and metabolic factors (model 2)]. The risk of CVD was gradually decreased in association with higher adherence to healthful-PDI, regardless of genetic susceptibility. The inverse associations of healthful-PDI with CVD were consistently observed in people with low GRS-MI [HR 0.85 (95% CI: 0.76, 0.94) in model 1; HR 0.88 (0.79, 0.97) in model 2] and those with high GRS-MI [HR 0.91 (0.82, 0.99) in model 1; HR 0.94 (0.86, 1.04) in model 2], without significant interactions (Pinteraction = 0.59 in model 1; Pinteraction = 0.66 in model 2). Similarly, higher healthful-PDI was related to a lower risk of CVD, regardless of low/high GRS-stroke. Adherence to healthy plant-based diets may be associated with a decreased incidence of CVD in the entire population, suggesting that plant-based dietary patterns may modify the risk of CVD, regardless of genetic susceptibility.

OBJECTIVE: Fibroblast growth factor 21 (FGF21) is involved in the regulation of energy balance and adipose metabolism. Our previous genome-wide association study identified genetic variants in the FGF21 region associated with macronutrient intake preference. We investigated whether the FGF21 genotype modified effects of weight-loss diets varying in macronutrient intake on changes in adiposity in a 2-year randomized diet intervention trial. RESEARCH DESIGN AND METHODS: We genotyped FGF21 rs838147 in 715 overweight or obese individuals who were assigned to one of four diets varying in macronutrient contents. A DEXA scan was performed to evaluate body composition. RESULTS: We observed a significant interaction between the FGF21 genotype and carbohydrate/fat intake on 2-year changes in waist circumference (WC), percentage of total fat mass, and percentage of trunk fat (P = 0.049, P = 0.001, and P = 0.003 for interaction, respectively). In response to the low-carbohydrate/high-fat diet, carrying the carbohydrate intake–decreasing C allele of rs838147 was marginally associated with less reduction in WC (P = 0.08) and significantly associated with less reduction of total fat mass (P = 0.01) and trunk fat (P = 0.02). Opposite genetic associations with these outcomes were observed among the high-carbohydrate/low-fat diet group; carrying the C allele was associated with a greater reduction of WC, total body fat mass, and trunk fat. CONCLUSIONS: Our data suggest that FGF21 genotypes may interact with dietary carbohydrate/fat intake on changes in central adiposity and body fat composition. A low-calorie, high-carbohydrate/low-fat diet was beneficial for overweight or obese individuals carrying the carbohydrate intake–decreasing allele of the FGF21 variant to improve body composition and abdominal obesity.

Obesity and abdominal obesity have been closely related to cardiovascular outcomes, and recent evidence has indicated that environmental and genetic factors act in concert in determining the risks of these conditions. Improving adherence to healthy lifestyle habits and healthy dietary patterns can at least partly counteract genetic variations related to risks of obesity and cardiovascular disease (CVD). Other factors, such as epigenetic alterations, may also modulate a relationship between genetic susceptibility and these disorders. In this review, we highlight data from recent studies on gene and environmental risk factors for obesity and CVD, and describe how these findings might inform understanding of the complex roles of interactions between genes and environmental factors in the development of obesity and CVD.