So far, the scientists have analyzed two million DNA variations in 15 genome-wide association studies with a total of more than 32,000 participants. The hereby identified candidate genes were validated in 14 further studies including 59,000 participants. In addition to the FTO and MC4R genes already known, it was now possible for six more obesity genes to be identified: TMEM18, KCTD15, GNPDA2, SH2B1, MTCH2, and NEGR1.

Gene expression analyses have shown that all six genes are active in brain cells. Also the previously known two obesity genes, FTO and MC4R, show a similar expression pattern; in case of the MC4R gene, a genotype-dependant influence on the behavior of appetite is already established. Scientists of the German National Genome Research Network (NGFN), Prof. H.-Erich Wichmann and Dr. Iris Heid from the Helmholtz Zentrum M nchen, Institute of Epidemiology, who lead the German participation of this consortium, emphasize: "Definitely, the two main causes for obesity are poor nutrition and lack of physical activity. But the biology of these genes suggests genetic factors underlying the different reaction of people to lifestyle and environmental conditions."

With the exception of the SH2B1 gene, which plays a role in the leptin signalling and thus in the regulation of appetite, none of the other five genes was hitherto discussed as obesity genes. Iris Heid and her collegue Claudia Lamina from the Ludwigs-Maximilians-Universit?¤t M nchen are enthused: "The purely statistical approach of the genome-wide association analysis can depict new aspects of the biology of weight regulation, which were previously unanticipated."

As a next step, the scientists evaluate other anthropometric measures, in order to shed light on different aspects of obesity. In addition, they will expand and include further studies into their analysis as they have realized that the individual studies are all too small, and only by means of collaboration, is it possible to achieve further success here.

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"It seems that an important job of SIRT6 is to restrain NF-kB and limit the expression of genes associated with aging," said Chang. "We've been interested in the activity of regulatory genes such as NF-kB during aging for several years now, and we were quite happy to find this very clear biochemical connection between these two pathways."

Young mice lacking the SIRT6 protein displayed elevated levels of NF-kB-dependent genes involved in immune response, cell signaling and metabolism - all potentially involved in the uniformly fatal aging-like condition that killed them within four weeks of birth. Tamping down the expression of the gene for NF-kB's SIRT-binding subunit allowed some of the mice to escape this fate.

"Mice lacking SIRT6 seem to hit some kind of a wall at around four weeks of age," said Chua, "when their blood sugar drops to a level barely compatible with life. Reducing NF-kB activity somehow allows the mice to get over this critical period and to live much longer. These mice provide a great new tool to study the effect of SIRT6-deficiency in much older animals than was possible before."

The researchers are now working to understand how NF-kB knows when and to what extent during an organism's lifetime to initiate the degenerative process and what role SIRT6 may play.

"It's a very provocative question," said Chang. "We've tied together two previously separate pathways in aging. Now we'd like to better understand what regulates that pathway."

Chang and Chua's co-authors on the study include graduate students Tiara Kawahara and Mara Damian; research associate Eriko Michishita, PhD; postdoctoral scholars Adam Adler, PhD, and Ron McCord, PhD; research assistants Elisabeth Berber, PhD, Meihong Lin and Lisa Boxer; and Stanford undergraduate Kristine Ongaigui.

The research was supported by the National Institutes of Health, the Department of Veterans Affairs, the California Breast Cancer Research Program, the American Cancer Society and the Paul B. Beeson Aging Research Program.

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