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

Anabel Perez-Gomez,Gregory Solis,Viktoriya Titova,Michael Petrascheck,Olivia Osborn,Natalie Weber,Alan To,Veronika Peterka,Maria Carretero

doi:10.1038/s41467-018-07684-y

Anabel Perez-Gomez, Gregory Solis + Show 7 more

Open Access

https://doi.org/10.1038/s41467-018-07684-y

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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.

Highlights

Antipsychotic (AP) drugs are used to treat psychiatric disorders but are associated with significant weight gain and metabolic disease
Follow up testing in mice shows that minocycline, an adjuvant drug identified in the C. elegans screen, blocks AP-induced hyperphagia, weight gain, and AP-induced hypothalamic gene expression in mice
Using our C. elegans based 96-well plate food-intake assay[23], we determined that various classes of drugs, including antihistamines, tricyclic antidepressants, and APs, known to induce hyperphagia in human patients[10,24], result in significantly increased food intake in C. elegans (Table 1)

Summary

Introduction

Antipsychotic (AP) drugs are used to treat psychiatric disorders but are associated with significant weight gain and metabolic disease. 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. We report that administration of APs to the small nematode C. elegans induces hyperphagia by a mechanism that is genetically distinct from normal, unstimulated food intake, termed basal feeding. We exploit this observation to screen 192 drugs for those that selectively suppress AP-induced hyperphagia. Our discovery based and hypothesis-free C. elegans screening strategy facilitates the identification of other potential adjuvant options, as well as gain deeper mechanistic understanding in to the mode of action of effective adjuvants like minocycline

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