An in vivo screening system for chemical modulators of eating behavior

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Project Summary Our application entitled ”An in vivo screening system for chemical modulators of eating behavior” has been written to respond to funding opportunity PA-16-374 entitled: “Assay Development and Screening to Discover Therapeutic or Imaging Agents for Diseases of Interest to the NIDDK”. This funding opportunity seeks to fund the development of phenotypic assays that allow for unbiased screens for molecules that modulate disease relevant endpoints. PA-16-374 specifically includes the use of model organisms (e.g. C. elegans) that can recapitulate important aspects of health-related outcomes. Excessive body weight gain is a common side effect of antipsychotic drugs and increases the risk for development of type 2 diabetes and metabolic syndrome. The prevalence of metabolic side effects contributes to the high rate of non-compliance with antipsychotic medication, which is a major challenge in the treatment of mental health. Increased food intake (hyperphagia) plays a large role in driving antipsychotic-induced weight gain but the mechanisms underlying the hyperphagic effect are unknown. Using our recently developed microtiter based food intake assay in C. elegans we find that antipsychotics such as clozapine and olanzapine also induce hyperphagia in C. elegans. Our genetic analysis revealed that basal food intake and antipsychotic induced hyperphagia are genetically distinct and that it is possible to suppress the antipsychotic side effect without affecting basal food intake. The proposed screen will identify potential adjuvant treatments that can suppress antipsychotic-induced hyperphagia. Screening 1,549 FDA approved drugs with optimized pharmaco- kinetics and safety, rather than compounds with unknown liabilities, provides the fastest route to testing potential adjuvant therapies in the clinic. As a proof of concept we conducted a small pilot screen of 197 FDA approved drugs in C. elegans and identified that minocycline suppressed antipsychotic-induced hyperphagia in worms. Importantly, our follow up studies show that minocycline treatment also suppresses hyperphagia and weight gain in mice and reverses changes in hypothalamic gene expression induced by olanzapine. The power of using model species separated by millions of years of evolution, further increase the potential for translatability of effects of potential adjuvants to human subjects. Our approach provides a fast and efficient route to identify potential adjuvant therapies that can be moved quickly to the clinic and is thus relevant to public health. As the global incidence of obesity and diabetes grows, the importance of mitigating the weight gain effects of antipsychotics becomes even more important. These studies are also highly relevant to the NIDDKs mission to prevent or ameliorate treatment-emergent side effects and delineate the mechanisms through which psychotropic medications produce adverse metabolic events.