2. Academic Validation
  3. A phenotypic Caenorhabditis elegans screen identifies a selective suppressor of antipsychotic-induced hyperphagia

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

  • Nat Commun. 2018 Dec 10;9(1):5272. doi: 10.1038/s41467-018-07684-y.
Anabel Perez-Gomez 1 2,  Maria Carretero 1 2,  Natalie Weber 3,  Veronika Peterka 3,  Alan To 1 2,  Viktoriya Titova 1 2,  Gregory Solis 1 2,  Olivia Osborn 4,  Michael Petrascheck 5 6
Affiliations

Affiliations

  • 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.
PMID: 30532051 DOI: 10.1038/s41467-018-07684-y
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.

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