Free Fatty Acid Receptor 4 Mediates the Beneficial Effects of n-3 Fatty Acids on Body Composition in Mice

As populations continue to age worldwide, sarcopenic obesity has heightened interest due to its medical importance. Although much evidence now indicates that n-3 fatty acids (FAs) may have beneficial effects on body composition including fat and muscle, their exact mechanisms have not yet been elucidated. Because free FA receptor 4 (FFA4) has been reported to be a receptor for n-3 FAs, we hypothesized that the protective role of n-3 FAs on body composition could be mediated by FFA4. To test this possibility, we generated mice overexpressing n-3 FAs but lacking FFA4 by crossing fat-1 transgenic (fat-1 (Tg+)) and FFA4 knockout (Ffar4 (-/-)) mice. Because fat-1 (Tg+) mice, in which n-6 is endogenously converted into n-3 FAs, contain high n-3 FA levels, they could be a good animal model for studying the effects of n-3 FAs in vivo. Male and female littermates were included in high-fat-diet- (HFD) and ovariectomy-induced models, respectively. In the HFD model, male fat-1 (Tg+) mice had a lower percentage of fat mass and a higher percentage of lean mass than their wild-type littermates only when they had the Ffar4 (+/+) not the Ffar4 (-/-) background. Female fat-1 (Tg+) mice showed less increase of fat mass percentage and less decrease of lean mass percentage after ovariectomy than wild-type littermates. However, these effects on body composition were attenuated in the Ffar4 (-/-) background. Taken together, our results indicate that the beneficial effects of n-3 FAs on body composition were mediated by FFA4 and thus suggest that FFA4 may be a potential therapeutic target for modulating sarcopenic obesity.