A phenotypic Caenorhabditis elegans screen identifies a selective suppressor of antipsychotic-induced hyperphagia

Anabel Perez-Gomez, Maria Carretero, Natalie Weber, Veronika Peterka, Alan To, Viktoriya Titova, Gregory Solis, Olivia Osborn () and Michael Petrascheck ()
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Anabel Perez-Gomez: The Scripps Research Institute
Maria Carretero: The Scripps Research Institute
Natalie Weber: University of California, San Diego
Veronika Peterka: University of California, San Diego
Alan To: The Scripps Research Institute
Viktoriya Titova: The Scripps Research Institute
Gregory Solis: The Scripps Research Institute
Olivia Osborn: University of California, San Diego
Michael Petrascheck: The Scripps Research Institute

Nature Communications, 2018, vol. 9, issue 1, 1-12

Abstract: Abstract Antipsychotic (AP) drugs are used to treat psychiatric disorders but are associated with significant weight gain and metabolic disease. Increased food intake (hyperphagia) appears to be a driving force by which APs induce weight gain but the mechanisms are poorly understood. Here we report that administration of APs to C. elegans induces hyperphagia by a mechanism that is genetically distinct from basal food intake. We exploit this finding to screen for adjuvant drugs that suppress AP-induced hyperphagia in C. elegans and mice. In mice AP-induced hyperphagia is associated with a unique hypothalamic gene expression signature that is abrogated by adjuvant drug treatment. Genetic analysis of this signature using C. elegans identifies two transcription factors, nhr-25/Nr5a2 and nfyb-1/NFYB to be required for AP-induced hyperphagia. Our study reveals that AP-induced hyperphagia can be selectively suppressed without affecting basal food intake allowing for novel drug discovery strategies to combat AP-induced metabolic side effects.

Date: 2018
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DOI: 10.1038/s41467-018-07684-y

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