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Severe obesity – a hereditary illness based on eating behavior

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This result was published in Nature Genetics on January 18th 2009 by a research group led by CNRS senior researcher Philippe Froguel and Inserm researcher David Meyre from the laboratory "Génomique et physiologie moléculaire des maladies métaboliques" (1), in association with their British colleagues from Imperial College.

This study, run in collaboration with French, Finnish, Swiss, Canadian and German researchers, has led to the discovery of three new genes that increase the risk not only of severe obesity but also ordinary weight gain in the population. It underlines that there is no difference between being overweight and other forms of obesity (mild, severe or massive).

Obesity is spreading throughout the world like an epidemic. For the first time in history, obesity-related health problems (like type 2 diabetes (2), heart disease and cancer) could reduce the life-expectancy of today’s children by several years compared with their parents’ generation. Even though the increase in the number of obese people over the two last decades is partially due to social causes (inactivity, junk food, etc.), heredity plays an important part in determining body weight (70% hereditary) and the occurrence of obesity, especially when this is severe and appears early in life.

First genetic map of obesity

Froguel’s team has been working for 15 years to better understand the molecular basis of type 2 diabetes and the obesity found in 80% of diabetics. Their work has revealed several genes responsible for monogenic forms of obesity and has demonstrated the essential role these genes play in appetite control. Since a full map was established of human genetic variations, it has been possible to study all the genes implicated in the genetic predisposition to obesity using DNA microarrays. With joint funding from the ANR (3), Région Nord Pas-de-Calais and the British Medical Research Council, French and British researchers have combed through the complete genomes of 2796 French volunteers, 1380 of which had severe familial obesity, compared with 1416 lean subjects. The genetic mutations most likely to cause obesity were then analyzed in 14,000 samples from French, Swiss, German and Finnish populations.

The scientists, led by Froguel and Meyre, first confirmed that the genes FTO and MC4R (4) played a major role in susceptibility to common obesity and weight gain in the population as a whole. These two genes work by controlling eating behavior.

Three new genes associated with obesity and weight gain identified

The researchers also found variations in the DNA close to the genes MAF and PTER (5), and directly in the coding sequence of the NPC1 gene. These genetic polymorphisms, widespread in European populations, alter the general population’s risk of severe obesity and weight gain throughout their lifetime. The NPC1 gene has more than 200 pathogenic mutations responsible for Niemann-Pick type C disease, a progressive neurodegenerative condition. Mice without NPC1, and which also have neurological disorders, also lose weight and have no appetite. The mutation associated with obesity could therefore directly induce an increase in the function of the NPC1 protein, such that it would work too well if the gene had mutated. As for the MAF gene, it codes for a particular protein involved in the differentiation of adipose tissue (tissue responsible for fat storage) and in the production of a digestive hormone involved in satiety and insulin secretion. The last gene (PRL) is more particularly associated with obesity and weight gain in adults. PRL produces prolactin, a hormone well known for its effect in stimulating lactation in women. Prolactin also plays a role in controlling the amount of food we consume.

Combined with the genetic approaches conducted on the general population, this work reveals that the study of family forms of obesity is particularly useful for understanding the genetic causes of obesity. They demonstrate the fundamental role of eating behavior in the regulation and evolution of human corpulence and in the incidence of severe childhood obesity. In the long term these results should allow the early identification of children at risk of obesity and the development of personalized preventive and therapeutic medical strategies.

These results were obtained with the help of volunteer families with obese children and/or adults. To continue the research, it is essential to have DNA from a maximum number of French subjects.

(1) CNRS/ Université Lille 2 Droit et Santé/ Institut Pasteur de Lille.
(2) This is a non-insulin dependant type of diabetes that occurs when the body is incapable of providing enough insulin for its needs or incapable of responding in the right way even when insulin is produced.
(3) The French National Research Agency
(4) Published by the team from Lilles in June 2007 and June 2008 in Nature Genetics.
(5) This gene has no known function at present.

Julien Guillaume | Quelle: alphagalileo
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