Grant: Project Grant

Nearly 2% of Canadians suffer from serious mental disorders, such as schizophrenia and bipolar disorder. Today, the most effective drugs for these psychiatric disorders are atypical antipsychotics (AAPs), but unfortunately, this treatment often results in severe metabolic dysfunctions, including obesity, impaired insulin sensitivity and high blood lipid levels. In addition, metabolic abnormalities can lead to heart disease, which is the number one cause of natural death in patients with schizophrenia. Therefore, new therapeutic strategies to counteract the metabolic adverse effects caused by AAPs are crucial to improve the clinical efficacy of AAPs. Our previous clinical and basic research identified an important factor called macrophage migration inhibitory factor (MIF), which was deeply involved in AAP-induced metabolic side-effects. Over the past eight years, we have been working to determine the role of fat derived MIF in modulating metabolic dysfunction. We found that MIF plays a key role in attenuating insulin action and increasing blood lipid levels. MIF also enhances lipid storage capacity in fat cells, leading to obesity. Interestingly, the absence of MIF in fat cells successfully counteracted the development of AAP-induced metabolic side-effects, suggesting that blocking fat-derived MIF would be a potential therapeutic approach to combat AAP-induced metabolic disorders. Selective activation of the neuronal receptor, trace amine-associated receptor (TAAR1) produces antipsychotic effects. Interestingly, our preliminary studies suggest that TAAR1 may have potential to limit MIF release in fat cells. Thus, we will investigate how TAAR1 downregulates the release of MIF in fat cells and its impact on metabolic dysfunction induced by the classic AAP, olanzapine by utilizing a combination of molecular and cellular biology techniques and physiological animal models. We believe that TAAR1 agonists will improve the clinical psychiatric treatment with AAPs.