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.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / toxicity
  • CCAAT-Binding Factor / genetics
  • Caenorhabditis elegans / genetics*
  • Caenorhabditis elegans Proteins / genetics*
  • Chemotherapy, Adjuvant
  • DNA-Binding Proteins / genetics
  • Eating / drug effects
  • Eating / genetics*
  • Gene Expression / drug effects
  • Gene Expression Profiling
  • Hyperphagia / chemically induced
  • Hyperphagia / drug therapy
  • Hyperphagia / genetics*
  • Hypothalamus / metabolism
  • Mice
  • Phenotype
  • Transcription Factors / genetics
  • Vemurafenib / pharmacology


  • Antipsychotic Agents
  • CCAAT-Binding Factor
  • Caenorhabditis elegans Proteins
  • DNA-Binding Proteins
  • Transcription Factors
  • nuclear hormone receptor NHR-25, C elegans
  • Vemurafenib