Title: Impact of chronic risperidone treatment on metabolic health of adolescent mice
Supervisor: Dr. David C. Wright
Committee members: Dr. Daniel Gamu, Dr. Brian Rodrigues
Abstract:
Background: Risperidone is an atypical antipsychotic commonly prescribed to children and adolescents for the management of schizophrenia and autism spectrum disorder, with increasing rates of off-label prescription of other mental illnesses. While efficacious at symptom management, risperidone treatment is associated with a number of concerning side effects, primarily hyperphagia, weight gain, hyperglycemia, impaired glucose tolerance, and other metabolic perturbations. Despite its growing popularity, the effects of chronic risperidone treatment in a pediatric preclinical model have yet to be elucidated. Robust pilot data from our lab suggests chronic risperidone treatment in young mice leads to metabolically healthy glucose excursions despite indices of insulin resistance and increased body weight and adiposity compared to their control counterparts. Whether this difference in glucose tolerance is due to increased secretion of insulin, and whether this is a direct effect of risperidone, is unknown.
Purpose: The purpose of my thesis is two-fold. Firstly, I aim to elucidate the differences in glucose tolerance between chronic risperidone treatment and high fat obesogenic diets in young mice. I hypothesize chronic risperidone treatment in young mice will lead to an improved glucose tolerance compared to their high fat diet (HFD)-fed counterparts and this will be linked to increases in glucose stimulated insulin secretion. Secondarily, I aim to determine whether the effects on glucose tolerance are a function of age. I hypothesize mature male and female mice will demonstrate worsened glucose tolerance following chronic risperidone treatment compared to their high fat diet-fed counterparts.
Methods: Three experiments will be conducted. Our first experiment will entail four-week old male and female C57BL/6J mice (N ≈ 24) randomized into either a 45% HFD control group (n ≈ 12) or 45% HFD + 50 mg/kg risperidone group (n ≈ 12). Mice will undergo six weeks of feeding with food and water provided ad libitum. After 6 weeks of treatment, mice will undergo a shortened 30-minute oral glucose tolerance test (OGTT). Mice will be immediately sacrificed to harvest serum and tissues (liver, skeletal muscle, brown adipose tissue, white adipose tissue) to provide a proxy of glucose stimulated insulin secretion. Our second experiment will follow the same feeding protocol as the first, followed by a shortened 30-minute insulin tolerance test. Likewise, serum and tissues will be harvested to assess insulin resistance and examine the tissue-specific insulin signaling pathway in response to exogenous insulin administration. Our final experiment will repeat the six-week feeding protocol, this time utilizing mature male and female C57BL/6J mice. Metabolic caging utilizing indirect calorimetry be used to assess differences in energy expenditure, oxygen consumption, carbon dioxide production, and locomotion between groups. Mice will undergo a full length OGTT to assess their response to an exogenous glucose challenge. End point measures will include differences in body weight, adiposity, food intake, tissue weights, serum insulin, glucose tolerance, and insulin resistance. As we are interested in whether there is a sexually dimorphic response, two-way analysis of variance (ANOVA) will be used to examine the effect of the drug and/or sex, and whether there is an interaction between the two.
Significance: Our project will provide insight on the effect of chronic risperidone treatment in a pediatric preclinical model and further enhance our understanding of risperidone’s metabolic effects.