Title: Growth Differentiation Factor 15 Associates with, but is not Responsible for, Exercise Induced Increases in Corticosterone and Indices of Fatty Acid Utilization in Mice
Thesis Supervisor: Dr. David Wright
Committee members: Dr. Cameron Mitchell, Dr. Michael Koehle
Defence Chair: Dr. Daniel Gamu
Abstract: Growth differentiation factor 15 (GDF15) is a stress-induced cytokine known for its anorexic effects mediated by the glial-cell-line-derived neurotrophic factor (GDNF) family receptor alpha-like (GFRAL) receptor located in the hindbrain. GDF15 is widely expressed in many tissues and increases in response to cellular stresses such as obesity, prolonged food restriction, and interestingly, exercise. The impact of post-exercise nutrition on GDF15 has not been examined, nor has the physiological role of increases in GDF15 with exercise been elucidated. The purpose of this thesis was to determine the impact of post-exercise nutrient availability on GDF15 and to use this as a model to explore associations between GDF15 and indices of whole-body fuel metabolism. I further wanted to examine if GDF15 was required for exercise-induced increases in corticosterone and markers of lipid utilization. I hypothesized that 1) with holding food following exercise would prolong increases in GDF15, 2) that there would be positive associations between GDF15, corticosterone and markers of lipid utilization and 3) that GDF15 would be required for exercise-induced increases in corticosterone and indices of fatty acid metabolism. Male mice were subjected to exhaustive treadmill running, or remained sedentary, for 2hrs. Mice were either sacrificed immediately post exercise or given ad libitum access to either a chow or high fat diet and tissues harvested 3 hours post. This was then repeated in wildtype/GDF15-/- male and female mice. Circulating concentrations of GDF15, corticosterone, fatty acids (NEFA), and beta hydroxybutyrate (BHB) were increased immediately post exercise and remained elevated when food was withheld during the recovery period. In contrast, the provision of either chow or a high fat diet during recovery resulted in decreases in these endpoints. While serum GDF15 was positively associated with corticosterone, BHB and NEFA, increases in these factors were similar in wildtype and GDF15-/- mice following exercise. The lack of a genotype effect was not secondary to compensatory changes in insulin, glucagon and epinephrine after exercise. The results of this thesis provide evidence that while GDF15 is associated with increases in indices of lipid utilization during and in the recovery from exercise, this is not a causal relationship.