David Wright

Atypical antipsychotics (APs) are considered the frontline treatment for individuals with schizophrenia, autism spectrum disorder, and a range of other mental health challenges. Risperidone is the most prescribed AP to children and adolescents, with high rates of off-label prescription. However, these drugs have serious metabolic consequences. Often, chronic treatment results in weight gain, insulin intolerance, and dyslipidemia, all of which have lasting impacts in adulthood. Despite the prevalence of childhood prescription, few studies have examined the effect in a model of young mice. Therefore, we aimed to elucidate the effects of chronic risperidone treatment on weight gain and indices of glucose and lipid metabolism in adolescent mice. We hypothesized that risperidone treatment in adolescent mice would result in weight gain and uncover a metabolic effect in both sexes. At 4 weeks of age male and female C57BL/6J mice were divided into either control or risperidone groups. Mice were given either a 45% high fat diet or a 45% high fat diet + 50 mg/kg of risperidone. Each group was kept on their respective diets for 6 weeks. Here, we show that chronic risperidone treatment in young mice leads to weight gain and increased adiposity in a sex-dependent manner, independent of changes in food intake. Risperidone treatment in both sexes resulted in improvements in insulin action, and improvements in glucose tolerance in male mice. Overall, our investigation demonstrates the sexually dimorphic effect of risperidone treatment on weight gain in adolescent mice and – in stark contrast to clinical data – leads to improved glucose homeostasis.

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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.

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