Deletion of FAT10 gene reduces body fat, slows down aging in mice

Researchers demonstrate that FAT10 coordinates immunity and metabolism to impact lifespan
March 24, 2014

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Boston, MA [March 24, 2014, 3:00 p.m. EDT] ─A single gene appears to play a crucial role in coordinating the immune system and metabolism, and deleting the gene in mice reduces body fat and extends lifespan, according to new research by scientists at the Jean Mayer USDA Human Nutrition Research Center (USDA HNRCA) on Aging at Tufts University and Yale University School of Medicine. Their results are reported online today in the Proceedings of the National Academy of Sciences.

Based on gene expression studies of fat tissue conducted at the USDA HNRCA, the Tufts University researchers initiated studies of the role of FAT10 in adipose tissue and metabolism. "No one really knew what the FAT10 gene did, other than it was 'turned on' by inflammation and that it seemed to be increased in gynecological and gastrointestinal cancers." said co-author Martin S. Obin, Ph.D., an adjunct scientist in the Functional Genomics Core Unit at the USDA HNRCA at Tufts University. "Turning off the FAT10 gene produces a variety of beneficial effects in the mice, including reduced body fat, which slows down aging and extends lifespan by 20 percent."

Typically, mice gain fat as they age. The authors observed that activation of the FAT10 gene in normal mice increases in fat tissue with age. Mice lacking FAT10 consume more food, but burn fat at an accelerated rate. As a result, they have less than half of the fat tissue found in normal, aged mice. At the same time their skeletal muscle ramps up production of an immune molecule that increases their response to insulin, resulting in reduced circulating insulin levels, protection against type 2 diabetes and longer lifespan.

The authors note that eliminating FAT10 will not fully address the dilemma of aging and weight gain. "Laboratory mice live in a lab under ideal, germ-free conditions," said Obin, who is also an associate professor at the Friedman School of Nutrition Science and Policy at Tufts University. "Fighting infection requires energy, which can be provided by stored fat. Mice without the FAT10 gene might be too lean to fight infection effectively outside of the laboratory setting. More research is needed to know how to achieve that balance in mice and then hopefully, at some point, people."

The possibilities for future research of FAT10 are exciting. Recent high-profile studies reported that FAT10 interacts with hundreds of other proteins in cells. Now the Tufts and Yale researchers have demonstrated that it impacts immune response, lipid and glucose metabolism, and mitochondrial function.

"Now there is dramatic road map for researchers looking at all of the proteins that FAT10 gets involved with," said co-first and corresponding author Allon Canaan, Ph.D., an associate scientist in the Department of Genetics at Yale. "Blocking what FAT10 does to coordinate immunity and metabolism could lead to new therapies for metabolic disease, metabolic syndrome, cancer and healthy aging, because when we knock it out the net result is mice live longer."

Canaan and colleagues initially developed the FAT10-deficient mouse to study the role of FAT10 in sepsis. In an attempt to increase sensitivity for sepsis, Canaan aged the FAT10 knockout mice and made the discovery that mice lacking the gene were lean and aged more slowly. The mice appear younger and more robust than comparably-aged normal mice, have better muscle tone, and do not develop age-related tumors.

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The co-first author of the study is Jason DeFuria, Ph.D., who conducted the research as a doctoral student under Obin in the Obesity Metabolism Laboratory at the USDA HNRCA at Tufts University. DeFuria, a graduate of the Friedman School, is now a postdoctoral researcher in the Division of Cancer Biology and Tissue Engineering at Tufts University School of Dental Medicine. The Yale investigators include senior author Sherman M. Weissman, Vincent Schultz, Montrell Seay, David Tuck, and Richard Flavell. Additional co-authors are Eddie Perelman of Ben-Gurion University of the Negev, and Michael Snyder of Stanford University.

This study was funded by the William Prushoff Foundation, NIH Grants to Obin (R01DK074979) and DeFuria (T32DK062032) and with funds from the U.S. Department of Agricultural-Agricultural Research Service contract 58-1950-7-70.

Canaan A; Defuria J; Perelman E; Schulz V; Seay M; Tuck D; Flavell R; Snyder M; Obin M; and Weissman S. "Extended Lifespan and Reduced Adiposity in Mice Lacking the FAT10 Gene." Proceedings of the National Academy of Sciences. Published online ahead of print March 24, 2014.

For three decades, the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University has studied the relationship between good nutrition and good health in aging populations. Tufts research scientists work with federal agencies to establish the USDA Dietary Guidelines, the Dietary Reference Intakes, and other significant public policies. The Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy at Tufts University is the only independent school of nutrition in the United States. The school's eight degree programs, which focus on questions relating to famine, hunger, poverty, and communications, are renowned for the application of scientific research to national and international policy.