An epidemic of obesity afflicts European populations, posing a major public health challenge due to the associated severe problems and inability to manage them. The project aims at improving understanding of interaction between nutrition (i.e. fat intake) and genetic variations and functions in obesity. Seven hundred and fifty obese and 150 reference subjects will be examined by a scrutiny of dietary habits and relevant life style aspects, a 3-day dietary standardisation at 37% of energy as fat, a 1-day clinical investigation with a test meal with 60% fat, and a 10-week hypocaloric dietary intervention (~ 600 kcal energy deficit per day), either with a low fat content (20-25% fat) or with a high fat content (40-45% fat). Metabolic and hormonal responses to the test meal, changes during the intervention period in body weight and composition, and in gene expression in adipose tissue will be related to genotypes of selected new candidate genes. Such knowledge may improve treatment and prevention of obesity.
The overall objective of the project is to elucidate the role in human obesity of interactions between macronutrient composition of the diet with particular emphasis on fat intake and specific genetic variants. It aims at combining clinical/physiological variables to the effects of a very high-fat test meal challenge and a long-term hypoenergetic low-fat or hypoenergetic high-fat diet with knowledge of genetic make up and expression levels of individual genes.
This objective can be divided into the following specific aims:
- Identification and characterisation of novel nutrient-sensitive candidate genes for obesity, i.e. genes in which variants result in differential responses in obesity-related physiological functions and in adipose tissue to nutrient challenges such as a high-fat meal and a long-term hypoenergetic alteration of dietary fat content.
- Assessment of the effects of the variants and combinations of variants in known and novel nutrient-sensitive genes on the response in obese subjects to a high-fat test meal in the physiological functions: appetite and satiety, energy expenditure and nutrient partitioning, and circulating obesity-related substrates, hormones and metabolites.
- Assessment of the combined effects the variants of novel and known nutrient-sensitive genes and a short- and long-term alterations in dietary fat content on the differential expression of selected functional genes in adipose tissue.
- Identification of predictors of the changes in body weight and composition of obese subjects during a long-term hypoenergetic low-fat or high-fat dietary intervention programme. These predictors may be: a) variants or combinations of variants of the nutrient-sensitive genes, b) the obesity-related life style factors, c) the differential physiological functions observed at the test meal challenge, d) the gene expression in adipose tissue, or e) gene-phenotype or gene-environment interactions based on combinations of these predictors.
This project is expected to increase in our understanding of the interaction between dietary fat and the genetic predisposition to obesity. This new knowledge will improve in several ways the basis for the ability to limit the development of the epidemic of obesity by more effective and more precisely targeted prevention and treatment.
More specifically, the expectation is to achieve more precise knowledge about, and improved understanding of:
- Genomic position and structure, functional variants, and regulation of several novel nutrient-sensitive genes that may be involved in the pathogenesis of obesity.
- The specific mechanisms underlying the well documented genetic predisposition to obesity, which is polygenic and probably heterogeneous with different genes playing a major role in different subsets of obese subjects.
- Genes actively involved in the regulation of metabolic efficiency, in excessive accumulation of fat in adipose tissue and in the changes in fat content of the adipose tissue induced by alterations of the dietary fat content.
- The complex role of fat intake in the pathogenesis of obesity by disclosing the specific nutrient-gene interactions both at a challenge of a single high-fat meal and during a long-term low-fat or high-fat dietary intervention.
- The inter-individual variation in the response to a fat challenge by evaluating the physiological responses to a high-fat test meal in relation to the specific genotypes of the obese subjects, which will characterise the obese subjects with regard to their ability to metabolise fat.
- The inter-individual variation in the changes in body weight and composition during a long-term hypoenergetic low-fat or high-fat dietary intervention.
It is envisaged that the results of this project may lay the grounds for:
- Development of a new obesity taxonomy, in which new modes of classification of subtypes of obesity are based upon their specific genotypes, and the nutrient-gene interaction emerging during the high-fat test meal or the hypoenergetic low-fat or high-fat dietary intervention programme.
- Development of diagnostic tools - on the basis of the genotyping and the responses to the challenge to a high-fat meal - that can discriminate obese subjects with respect to effectiveness of a long-term hypoenergetic low-fat or high-fat dietary intervention allowing accurate targeting of this intervention and delineation of obese subjects in whom other means of intervention are needed.