Obesity: Spotlight on Nutrigenomics


What is nutrigenomics? “It involves using molecular biology techniques to characterize biomarkers in the field of nutrition,” explains Dominique Langin, Director of U586 "Obesity Research Unit" in Toulouse. “These can be markers of an individual’s nutritional status, certain nutritional pathologies like obesity, or predictors of their progression. We are truly at the intersection of the patient's genes and their environment.” Thus, nutrigenomics seeks to answer the thorny question: what variations in the environment and genetic makeup induce responses at the level of gene expression, and how does this occur? Here’s a closer look at this rapidly growing discipline...


"The interest in adipose tissue as a fully-fledged endocrine tissue is very new," indicates Denis Lairon from U476 "Human Nutrition and Lipids: Bioavailability, Metabolism, and Regulation" in Marseille. "And it has only been a little over a decade since we discovered that lipids are not only essential as a source of energy but also very fine regulators of gene expression. Nutrigenomics is still in its infancy, and its explosion is primarily due to the developments of the tools available to us: it’s a bit like going from a 2CV to a Formula 1 in just a few years!” His team is very involved at the European level: it is part of the NuGO (European Nutrigenomics Organisation) network, which includes 23 teams across the continent to develop post-genomic technologies; furthermore, it participates in the integrated project of the 6th PCRDT LipGene, which aims to understand how differences in the composition of dietary lipids interact with the human genome to influence the development of metabolic syndrome.


"These European collaborations are very promising and interesting. However, they also require substantial resources, with access to sufficiently large cohorts and data processing by the tens or even hundreds of thousands," continues the researcher from Marseille. This concern is echoed by Karine Clément from U755 "Nutrition and Obesity: Genetic and Transcriptomic Approaches" (Hôtel-Dieu, Paris): “In nutrigenomics, our main tools are DNA chips and quantitative RT-PCR. These are incredible tools, but they generate such large quantities of data that we have had to recruit many bioinformaticians and develop original software tools."


Projects and Partnerships Galore


The hypothesis underlying the work of all Inserm teams involved in nutrigenomics is that obesity is an adaptation disease related to changes in lifestyle. "In short, it seems that obesity encompasses a set of adaptive mechanisms in the organism that reprogram its gene expression machinery to metabolize new nutrients or excess nutrients," explains Hubert Vidal from U449 "Molecular Mechanisms of Diabetes" in Lyon, who co-leads the team "Nutritional Regulation of Gene Expression" with Martine Laville. This team has launched the national NUTROGENE project, which investigates these changes in gene expression during clinical intervention trials: subjects, either healthy or overweight, undergo modifications in nutritional intake either qualitatively—in the NUTROGENE 1 trial, where the ω6/ω3 ratio is brought to 5/1 in an isocaloric manner by adding canola oil and fatty fish three times a week—or quantitatively with NUTROGENE 2, a hyper-nutrition diet that increases energy intake by 760 kcal/day in the form of lipids. "These nutritional protocols, under conditions close to everyday life, are being carried out with the CRNH (Center for Human Nutrition Research) in Lyon, directed by my colleague Martine Laville. They are funded as part of the 2004 regional PHRC (Hospital Clinical Research Program) and the National Research Program in Human Nutrition (PRNH)."


Once again, participation in major European projects makes perfect sense. The teams of Hubert Vidal, Dominique Langin, and Karine Clément are indeed closely collaborating within the Diogenes ("Diet, Obesity and Genes") project of the 6th PCRDT, which includes 29 teams, and of which Dominique Langin is the coordinator for the nutrigenomics component. “For this project, our three units presented themselves under a single Inserm label, Karine Clément rejoices. The Toulouse-Lyon-Paris axis forms a single block, which gives us much more strength.” Hubert Vidal adds, “This works very well because we are highly complementary: Dominique Langin focuses on the influence of low-calorie diets and physical exercise in obese individuals, Karine Clément pays special attention to the complications of obesity, and we concentrate on the modifications in nutritional intake. We form a very functional network through the Consortium "Research Network in Nutrition" created in 2002 within the ATC Nutrition (Concerted Thematic Action).” This is coordinated by Claudine Junien from U781 "Genetics and Epigenetics of Metabolic, Neurosensory and Developmental Diseases" (Necker, Paris), who is more interested in epigenetic programming during fetal and post-natal development, especially in metabolic syndrome (see article below). In addition to these four research units, it relies on bioinformatician-statistician researchers (Jean-Daniel Zucker from U755 and Jean-Philippe Jais from Paris V) and on active collaborations with several clinical services and genomics centers. “We meet and exchange a lot, creating a small but very active circle that publishes well, with very good international visibility.”


"It is not insignificant that our three laboratories find themselves, in this DIOGENES project, coordinating all genomic gene expression activities in nutrition at the European level," emphasizes Dominique Langin. "This reflects the good health of Inserm in this field. This vitality is also found in another technological development project of the 6th PCRDT, MolPAGE (Molecular phenotyping to accelerate genomic epidemiology), which aims to find new molecular tools for phenotyping, this time in diabetes. We bring our expertise regarding adipose tissue, particularly in the quality of biopsy procedures, the miniaturization of samples, and the analysis of gene expression. In this regard, we greatly benefit from our partnership with the Franco-Czech clinical research laboratory on obesity, which associates Inserm with Charles University in Prague, which I co-direct with Vladimir Stich since its inauguration by Inserm’s Director General, Christian Bréchot, in 2003."


From Dream to Reality…


What can be the concrete applications of discovering these famous biomarkers? “Industrials are very interested in advancements in nutrigenomics,” emphasizes Hubert Vidal. “Our better understanding of the adaptive phenomena at play in obesity unveils new proteins, new 'sensors' of environmental changes. Ideally, we could imagine redirecting the organism's response. However, initially, the industry plans to use these sensors as pharmaceutical targets by developing agonists or inhibitors of these proteins.” Another major challenge is the individualization of nutritional recommendations. Thus, Dominique Langin believes that "all the tools under development tend towards this direction, whether it be nutrigenomics, proteomics, or metabolomics.” In the long term, the characterization of biomarkers could therefore allow for predicting susceptibility to obesity based on a defined environment, as well as the risks of associated complications. “Nutrigenomics will undoubtedly influence clinical biology. We can hope to one day have markers as telling as blood glucose in diabetes or the profile of plasma lipid lipoproteins in cardiovascular diseases. This is extremely important in the field of obesity, which lacks markers and which will condition clinical management.” “The personalization of recommendations is a very 'hot' topic at the European level,” adds Denis Lairon. “Until now, they could not take individual specifics into account, but perhaps in about ten years, we will be able to provide more targeted and relevant advice. We may even consider detecting signs of susceptibility from a very young age and offering lifestyle strategies without delay.” But will this "risk mapping" not raise profound ethical questions? “We are at the stage of transitioning from dream to reality. Certainly, there will be debate, and it will be up to citizens to be involved and choose whether or not to use this technology very early on. It will no longer be a scientific problem, but a societal issue…”


Inherited Gene Modifications


In recent years, food has been considered from a different angle: the interactions of nutrients with genes. Nutrigenetics studies how genetic variations (polymorphisms) in the gene sequence—our genetic heritage—modulate responses to food. “The ‘obesity tsunami’ in the United States can thus be explained by nutrigenetics: today’s Americans descend from populations that fled famines. They have therefore accumulated 'good' genes that store but which have now become obsolete,” recounts Claudine Junien. Nutrigenomics, on the other hand, focuses on understanding how nutrients modulate gene expression. Nutrients contribute, through the remodeling of chromatin—more or less compacted thanks to theoretically reversible epigenetic modifications—to the activation or extinction of one or several genes in different tissues. The overall response to nutrients is the result of these two types of interactions. At all stages of life, foods interfere with gene expression. During fetal life, interferences with foods or metabolic disturbances in the mother can lead to anomalies in the development of tissues and organs over time, sometimes resulting in irreversible anomalies regarding size and/or the number of cells that compose it or its functions. This "point of no return," since the organ will be deficient, will result in a greater susceptibility to certain diseases. This susceptibility could be potentially accentuated by the presence of predisposition genes. Then, under the influence of an inadequate diet or behaviors, this innate and/or acquired susceptibility will lead, in adulthood, to the gradual emergence of diseases such as cardiovascular diseases, diabetes, or obesity. The placenta, the nourishing partner of the fetus for many months, could be a mirror of the nutritional pathway of the fetus during intrauterine development. Initially analyzing animal models subjected to variations in diet during