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Nat Commun. 2018 Dec 10;9(1):5272. doi: 10.1038/s41467-018-07684-y.

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

Author information

1
Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
2
Department of Neuroscience, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA.
3
Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA.
4
Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA, 92093, USA. oosborn@ucsd.edu.
5
Department of Molecular Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA. pscheck@scripps.edu.
6
Department of Neuroscience, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA, 92037, USA. pscheck@scripps.edu.

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.

PMID:
30532051
PMCID:
PMC6288085
DOI:
10.1038/s41467-018-07684-y
[Indexed for MEDLINE]
Free PMC Article

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