Power point presentation of the NUGENOB project
An epidemic of obesity afflicts the European populations posing a major public health challenge.
The project aims at improving the understanding of the interaction between nutrition — i.e. fat intake — and genetic variations and functions in obesity. Obese and lean subjects (750 and 115) from eight European cities will be examined by a scrutiny of dietary habits and life-styles, a one-day clinical investigation programme including a high-fat test meal followed by a 10-week hypocaloric dietary intervention with either high or low fat content.
Metabolic and hormonal responses to the test meal, changes in body weight and composition, and in adipose tissue gene expression will be related to genotypes of selected known and novel candidate genes.
The objective of the project is to improve understanding of the role of interaction
between nutrition, especially fat intake, and genetic variations in obesity,
which may be the basis for revision of dietary guidelines.
The aims are to:
1) identify and characterise novel nutrient-sensitive candidate genes for obesity,
2) assess differential gene expression in adipose tissue in relation to the
acute intake of a high fat meal as well as long term intake of a hypocaloric
diet with either a high or a low fat content,
3) assess effects of functional variants of the candidate genes on physiological
responses in obese subjects to a high-fat test meal: appetite, energy expenditure,
partitioning, and circulating obesity related hormones and metabolites, and
4) identify on this basis predictors of changes in body weight and composition
during dietary intervention, including changes in fat intake
In eight European cities, we define source populations from which we select the study population of a total of 750 obese and 115 normal weight reference subjects. All subjects will be invited to a scrutiny of the dietary habits and other life style aspects of relevance for obesity, a 3-day dietary standardisation at 37% of energy fat, and a 1-day clinical investigation with a test meal challenge with 60% fat.
Finally the obese subjects will be randomised to a 10-week intervention programme consisting of a hypocaloric diet (~ 600 Kcal energy deficit per day), either with a low fat content (20-25% fat) or with a high fat content (40-45% fat).
During the 1-day investigation we assess the physiological responses to the test meal in appetite, energy expenditure and nutrient partitioning, and circulating obesity-related substrates, hormones, and metabolites. Before the test meal, weight, height, waist-hip ratio, body composition measurement, and biopsies from the subcutaneous adipose tissue will be done. All of these measures are repeated following the 10 week intervention program in obese subjects.
Changes in expression of relevant candidate genes in adipose tissue are quantified
by mRNA measurements. Novel relevant, putatively nutrition-sensitive candidate
genes will be identified, cloned, sequenced, and analysed for functional variants
and mutations using currently available techniques for molecular genetics. A
special feature of this project is searching for candidate genes by cDNA-chips
technology applied to the adipose tissue before and after the test meal and
the intervention programme.
Using blood sample DNA from the entire study population, the genotypic distribution of the functional variants of the relevant candidate genes will be determined and related to the responses to the test meal and the intervention programme.
All data on the study population will be gathered in one common databank and
statistical analyses will be carried out as a basis for reporting and conclusions
of the study.
The results will be disseminated both in the scientific community and in the public arena both internationally and nationally.
Expected achievements
This project is aiming 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:
1. Genomic position and structure, functional variants, and regulation of several novel nutrient-sensitive genes that may be involved in the pathogenesis of obesity.
2. 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.
3. 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.
4. 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.
5. 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.
6. The inter-individual variation in the changes in body weight and composition
during a long-term hypocaloric 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 hypocaloric 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 hypocaloric 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.
progress in the project:The project started at March1, 2001.
In order to assure the same, standardised investigative procedures in
the clinical the project partners have made a set of isolated standard
operational procedures for all aspects of the project.
In eight European cities (Copenhagen, Maastricht, Stockholm,
Nottingham, Prague, Paris, Pamplona and Toulouse) a source and a study population
has been defined.
By October 31, all of the ~ 750 obese and ~ 115 lean subjects had
completed the screening and the 1-day clinical investigation. All obese
subjects had been randomised to either the high fat or the low fat
hypocaloric intervention.
The intervention was completed for the last subjects in February 2003. All blood analyses were completed in the summer 2003. Genotyping and gene expression is expected to be completed in February 2004. Several scientific papers are currently under preparations. For further information about the results see 'disseminations'.