A viable hypomorphic Arnt2 mutation causes hyperphagic obesity, diabetes and hepatic steatosis

Emre E Turer, Miguel San Miguel, Kuan Wen Wang, William McAlpine, Feiya Ou, Xiaohong Li, Miao Tang, Zhao Zang, Jianhui Wang, Braden Hayse, Bret Evers, Xiaoming Zhan, Jamie L Russell, Bruce A Beutler

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Aryl hydrocarbon receptor nuclear translocator 2 (ARNT2) is a member of the basic helix-loop-helix/PER-ARNT-SIM (bHLH/PAS) transcription factor family. ARNT2 heterodimerizes with several members of the family, including single-minded homolog-1 (SIM1) and neuronal PAS domain protein 4 (NPAS4), primarily in neurons of the central nervous system. We screened 64,424 third-generation germline mutant mice derived from N-ethyl-N-nitrosourea (ENU)-mutagenized great-grandsires for weight abnormalities. Among 17 elevated body weight phenotypes identified and mapped, one strongly correlated with an induced missense mutation in Arnt2 using a semidominant model of inheritance. Causation was confirmed by CRISPR/Cas9 gene targeting to recapitulate the original ENU allele, specifying Arg74Cys (R74C). The CRISPR/Cas9-targeted (Arnt2R74C/R74C) mice demonstrated hyperphagia and increased adiposity as well as hepatic steatosis and abnormalities in glucose homeostasis. The mutant ARNT2 protein showed decreased transcriptional activity when coexpressed with SIM1. These findings establish a requirement for ARNT2-dependent genes in the maintenance of the homeostatic feeding response, necessary for prevention of obesity and obesity-related diseases.

Original languageEnglish (US)
JournalDisease models & mechanisms
Volume11
Issue number12
DOIs
StatePublished - Dec 18 2018

Keywords

  • ENU
  • Hyperphagia
  • N-ethyl-N-nitrosourea
  • Obesity

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)

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