Fatty Acids Increase GDF15 and Reduce Food Intake Through a GFRAL Signaling Axis

In contrast to the well-defined biological feedback loops controlling glucose, the mechanisms by which the body responds to changes in fatty acid availability are less clearly defined. GDF15 suppresses the consumption of diets high in fat but is paradoxically increased in obese mice fed a high-fat diet. Given this interrelationship, we investigated whether diets high in fat could directly increase GDF15 independently of obesity. We found that fatty acids increase GDF15 levels dose-dependently with the greatest response observed with linolenic acid. GDF15 mRNA expression was modestly increased in the gastrointestinal tract, however, kidney GDF15 mRNA was ~1000-fold higher and was increased by over 3-fold with subsequent RNAscope analysis showing elevated expression within the cortex and outer medulla. Treatment of wildtype mice with linolenic acid reduced food intake and body mass, however, this effect was disappeared in mice lacking the GDF15 receptor GFRAL. An equal caloric load of glucose did not suppress food intake or reduce body mass in either WT or GFRAL KO mice. These data indicate that fatty acids such as linolenic acid increases GDF15 and suppresses food intake through a mechanism requiring GFRAL. These data suggest that a primary physiological function of GDF15 may be as a fatty acid sensor designed to protect cells from fatty acid overload.