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 "G?©nomique et physiologie mol?©culaire des maladies m?©taboliques" (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 obesityFroguel'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), R?©gion 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 identifiedThe 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 consumebined 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/ Universit?© Lille 2 Droit et Sant?©/ 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.

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While RNAi has profoundly accelerated the ability of scientists to probe and interrogate cells in the Petri dish, therapeutic breakthroughs have proved far more problematic. Researchers have had a difficult time delivering these tiny RNA molecules and ensuring that they actually penetrate the desired cells and tissues in a living organism.

Modifying a delivery technique that Lieberman developed in 2005, she and postdoctoral fellow Yichao Wu and junior researcher Deborah Palliser (who now heads her own laboratory at Albert Einstein College of Medicine) treated mice with strands of RNA that were fused to cholesterol molecules, which made it possible for the molecules to pass through the cell membranes. When applied in the form of a topical solution, these RNA molecules could then be fully absorbed into the vaginal tissue, protecting the mice against a lethal dose of administered virus.

One RNA molecule in the topical solution targeted a herpes gene called UL29, which the virus needs to replicate. Knocking out UL29 inactivates the virus.

Another RNA molecule targeted Nectin-1, a surface protein found on cells in the vaginal tissue. Nectin-1 acts as a kind of host gatekeeper to which the virus binds to pass into the cell. Without Nectin-1, the virus simply can't infect cells.

Either RNA molecule delivered by itself would be sufficient to block the virus, but together in this RNAi cocktail, the host tissue becomes like a fortress that pulls up the drawbridge to block the enemy's entrance, and also has a full-fledged battle plan to slaughter the enemy if they make it through.

"As far as we could tell, the treatment caused no adverse effects, such as inflammation or any kind of autoimmune response," says Lieberman. "And while knocking out a host gene can certainly be risky, we didn't see any indication that temporarily disabling Nectin-1 interfered with normal cellular function."

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