June 29th, 2015
Nomen omen, destiny in a name. So it seems for the gene that was called FAT10 at the time of its discovery, and not because of any relation to adiposity, but because it lay next to another gene known as HLA-F: from here its imaginative name F Adjacent Transcript 10.
The product of this gene is known to control protein stability and to be involved in immunity since its expression is upregulated by some inflammatory molecules, but its specific functions are obscure. Now, Canaan and colleagues from Yale University have discovered that FAT10 regulates lipid metabolism and longevity, as reported in their study published this week in PNAS.
The scientists created a mouse model lacking FAT10 gene (knockout mouse, KO) and examined the consequences of FAT10 absence. The first surprising observation was that FAT10 deletion increased mice longevity while preserving their health: the lifespan of KO mice was 20% longer compared to that of normal, wild-type mice, the animals maintained vigor during aging, and did not develop age-related tumors.
In addition, the researchers observed that KO mice were generally leaner than normal animals despite similar feeding habits and activity, because they tended to expend more energy per day than wild type mice. In the absence of FAT10 in fact mice preferentially metabolized fat rather than carbohydrates, which led to a significant decrease in their fat mass.
The scientists also found that KO mice had increased metabolism in skeletal muscles during normal locomotor activity, comparable to that induced by training. Lastly, their muscles contained lower levels of several inflammatory mediators with respect to normal animals, and higher levels of the antinflammatory molecule IL-10, indicating that deletion of FAT10 opposed the onset of inflammation.
Besides these effects on fat metabolism and the production of inflammatory factors, the lack of FAT10 was associated with lower blood levels of glucose and insulin, and increased insulin activity.
Thus, reduced body fat, increased metabolism and insulin sensitivity, and decreased propensity to inflammation induced by the loss of FAT10, all contributed to maintain mice in healthy conditions and to extend their longevity.
If these are the consequences of FAT10 deletion, it follows that in normal individuals functional FAT10, whose levels increase with aging, has the opposite effects: namely, it promotes fat accumulation, inflammation, insulin resistance, and it reduces muscle metabolism, predisposing to the development of pathological states as age advances.
What’s the meaning of these findings in relation to human health?
The scientists suggest that if FAT10 performs similar functions in humans, its deleterious effects can be exacerbated by a sedentary lifestyle and unbalanced nutrition. In fact, as an individual grows older, FAT10 would reduce energy metabolism, in particular lipid breakdown, increase his susceptibility to inflammatory states, and promote obesity and age-related diseases.
On the other hand, precisely because of its diverse effects, FAT10 is an interesting, potential therapeutic target: drugs inhibiting its functions would act at multiple levels, rebalancing energy and glucose metabolism and body fat-mass, and controlling inflammation. Such drugs could be useful not only to prevent and treat obesity, but also to maintain an organism in a general healthy state while aging, thus preserving its vigor and increasing the length of a sound, disease-free life.
Canaan, A., DeFuria, J., Perelman, E., Schultz, V., Seay, M., Tuck, D., Flavell, R., Snyder, M., Obin, M., & Weissman, S. (2014). Extended lifespan and reduced adiposity in mice lacking the FAT10 gene Proceedings of the National Academy of Sciences DOI: 10.1073/pnas.1323426111
Mice, longevity, fat, metabolism, fat10, gene, inflammation, aging