Extended lifespan and reduced adiposity in mice lacking the FAT10 gene

Allon Canaan, Jason DeFuria, Eddie Perelman, Vincent Schultz, Montrell Seay, David Tuck, Richard A. Flavell, Michael P. Snyder, Martin S. Obin, and Sherman M. Weissman
PNAS published ahead of print March 24, 2014 https://doi.org/10.1073/pnas.1323426111

  1. Contributed by Sherman M. Weissman, December 24, 2013 (sent for review October 29, 2013)

Significance

For the first time we describe a physiological role for HLA-F adjacent transcript 10 (FAT10) in metabolism, obesity, and aging in mammals. We show that FAT10 knockout prevents the development of age-associated obesity in mice while extending lifespan and vigor without the appearance of deleterious developmental effects. In addition, we did not observe an increase in cancer incidence. If the role of FAT10 in humans is similar to mice, then targeting of FAT10 may hold promising therapeutic impact for the treatment of various diseases including obesity and obesity-related diseases and aging associated diseases.

Abstract

The HLA-F adjacent transcript 10 (FAT10) is a member of the ubiquitin-like gene family that alters protein function/stability through covalent ligation. Although FAT10 is induced by inflammatory mediators and implicated in immunity, the physiological functions of FAT10 are poorly defined. We report the discovery that FAT10 regulates lifespan through pleiotropic actions on metabolism and inflammation. Median and overall lifespan are increased 20% in FAT10ko mice, coincident with elevated metabolic rate, preferential use of fat as fuel, and dramatically reduced adiposity. This phenotype is associated with metabolic reprogramming of skeletal muscle (i.e., increased AMP kinase activity, β-oxidation and -uncoupling, and decreased triglyceride content). Moreover, knockout mice have reduced circulating glucose and insulin levels and enhanced insulin sensitivity in metabolic tissues, consistent with elevated IL-10 in skeletal muscle and serum. These observations suggest novel roles of FAT10 in immune metabolic regulation that impact aging and chronic disease.

Footnotes

  • ↵1A.C. and J.D. contributed equally to this work.

  • ↵2To whom correspondence should be addressed. E-mail: allon.canaan{at}yale.edu.

  • Author contributions: A.C., M.S.O., and S.M.W. designed research; A.C., J.D., and M.S. performed research; R.A.F. and M.P.S. contributed new reagents/analytic tools; A.C., J.D., E.P., V.S., D.T., R.A.F., M.S.O., and S.M.W. analyzed data; A.C., M.S.O., and S.M.W. wrote the paper; and A.C. discovered the mouse phenotype.

  • The authors declare no conflict of interest.

  • This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10.1073/pnas.1323426111/-/DCSupplemental.

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FAT10 impacts adiposity and aging
Allon Canaan, Jason DeFuria, Eddie Perelman, Vincent Schultz, Montrell Seay, David Tuck, Richard A. Flavell, Michael P. Snyder, Martin S. Obin, Sherman M. Weissman
Proceedings of the National Academy of Sciences Mar 2014, 201323426; DOI: 10.1073/pnas.1323426111
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