RRC ID 59397
Author Perez-Gomez A, Carretero M, Weber N, Peterka V, To A, Titova V, Solis G, Osborn O, Petrascheck M.
Title A phenotypic Caenorhabditis elegans screen identifies a selective suppressor of antipsychotic-induced hyperphagia.
Journal Nat Commun
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.
Volume 9(1)
Pages 5272
Published 2018-12-10
DOI 10.1038/s41467-018-07684-y
PII 10.1038/s41467-018-07684-y
PMID 30532051
PMC PMC6288085
MeSH 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
IF 11.878
Times Cited 5
C.elegans tm1325 tm1062 tm1392 tm4257 tm4760 tm3224 tm1265 tm2908 tm3026