GDF15 associates with, but is not responsible for, exercise-induced increases in corticosterone and indices of lipid utilization in mice

Growth differentiation factor 15 (GDF15) is a stress-induced cytokine that increases with exercise and is thought to increase corticosterone and lipid utilization. How postexercise nutrient availability impacts GDF15 and the physiological role that GDF15 plays during and/or in the recovery from exercise has not been elucidated. The purpose of this investigation was to examine how postexercise nutrient availability impacts GDF15 and to use this as a model to explore associations between GDF15, corticosterone, and indices of lipid and carbohydrate metabolism. In addition, we explored the causality of these relationships using GDF15-deficient mice. Male and female C57BL/6J mice ran for 2 hours on a treadmill and were euthanized immediately or 3 hours after exercise with or without access to a chow diet. In both sexes, circulating concentrations of GDF15, corticosterone, nonesterified fatty acids (NEFA), and beta-hydroxybutyrate (BHB) were higher immediately postexercise and remained elevated when food was withheld during the recovery period. While serum GDF15 was positively associated with corticosterone, BHB, and NEFA, increases in these factors were similar in wild-type and GDF15^-/- mice following exercise. The lack of a genotype effect was not explained by differences in insulin, glucagon, or epinephrine after exercise. Our findings provide evidence that while GDF15 is associated with increases in corticosterone and indices of lipid utilization this is not a causal relationship.<b>NEW & NOTEWORTHY</b> Circulating growth differentiation factor 15 (GDF15) increases during exercise, but the physiological role that it plays has not been elucidated. Recent data suggest that GDF15 regulates corticosterone and lipid utilization. Here we demonstrate that postexercise nutrient availability influences GDF15 in the recovery from exercise and GDF15 is associated with corticosterone and indices of lipid utilization. However, the associations were not causal as exercise-induced increases in fatty acids, beta-hydroxybutyrate, and corticosterone were intact in GDF15^-/- mice.