Meagan Arbeau’s MSc Thesis Proposal (Zoom)

Title: The impact of post exercise nutrition on growth differentiation factor 15 in mice

Supervisor: Dr. David Wright
Committee members: Dr. Cameron Mitchell & Dr. Michael Koehle


Growth differentiation factor 15 (GDF15) is a novel pharmacological treatment target for the treatment of metabolic disease because of its anorexic effects. GDF15 is a member of the transforming growth factor-β (TGFβ) superfamily circulating as a ~25kDa homodimer (1). GDF15 is abundantly expressed in several tissues including the liver, adipose tissue, intestine, kidneys, and placenta (1,2). Circulating levels of GDF15 increase in humans and rodents during exercise (1) and is thought to potentially be mediated through AMPK activation and/or endoplasmic reticulum (ER) stress (3). Additionally, high-saturated-fat diet induces ER stress by causing an imbalance between protein-folding and ER capacity (4). The exposure of a high fat diet after exercise should induce ER stress, and therefore potentially increase circulating GDF15 and GDF15 expression (4,5). GDF15 signals through the glial-cell- line-derived neurotrophic factor family receptor -like (GFRAL) receptor located in the hindbrain (5) and reduces food intake and/or the preference for foods higher in fat (2,6,7) while also increasing sympathetic outflow (8). In addition to exercise, saturated fatty acids can also increase GDF15 (9). It is currently unknown if post exercise nutrition, specifically a high fat diet. alters the expression of circulating concentrations of GDF15. Therefore, the purpose of my proposed research is to investigate the interactions between exercise and post exercise nutrition on GDF15. I hypothesize that fasted and mice fed a high saturated fat diet following exercise will prolong elevations in GDF15 and this will occur in parallel with changes in markers of ER and energetic stress. In this study I will use male C57B6/J mice (N=40) that will be randomized into a sedentary group (n=8) and an exercise group (n=32). Mice in the exercise group will be further randomized into one of three diet groups; fasted, high fat lard based (60% energy derived from fat), and chow. Mice in the exercise group will be familiarized to the motorized rodent treadmill for 2 consecutive days before maximum running speed is assessed (5). Mice will run on a rodent treadmill for 2-hours at 70% maximum running speed at an incline of 5% (5). Immediately following exercise, serum, liver, adipose tissue, and triceps muscle will be harvested from a cohort of mice (n=8) while the remaining mice will be given ad libitum access to the various diets for 3-hours. An additional group of exercised mice will have their food removed during the recovery period. The total amount of food consumed in each diet group during recovery will be measured and serum, liver, adipose tissue, and skeletal muscle harvested for the determination of circulating GDF15 and tissue specific changes in GDF15 mRNA and ER/energetic stress markers. The proposed studies will provide insight into the interactions between exercise and post exercise nutrition in the regulation of GDF15, a signaling factor which has been proposed to mediate the beneficial effects of exercise on fuel metabolism. This research will have significant impacts on weight loss and addressing the obesity crisis and its associated negative effects, while offering a better quality of life.