# An in vivo screening system for chemical modulators of eating behavior

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2021 · $539,778

## Abstract

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.

## Key facts

- **NIH application ID:** 10146363
- **Project number:** 5R01DK117872-04
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** Olivia D Osborn
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $539,778
- **Award type:** 5
- **Project period:** 2018-08-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10146363

## Citation

> US National Institutes of Health, RePORTER application 10146363, An in vivo screening system for chemical modulators of eating behavior (5R01DK117872-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10146363. Licensed CC0.

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