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

1 Citation (Scopus)

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

Fingerprint

Aryl Hydrocarbon Receptor Nuclear Translocator
Medical problems
Clustered Regularly Interspaced Short Palindromic Repeats
Obesity
Mutation
Liver
Genes
Ethylnitrosourea
Hyperphagia
Gene Targeting
Adiposity
Neurology
Missense Mutation
Causality
Neurons
Proteins
Homeostasis
Transcription Factors
Central Nervous System
Alleles

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)

Cite this

A viable hypomorphic Arnt2 mutation causes hyperphagic obesity, diabetes and hepatic steatosis. / Turer, Emre E; San Miguel, Miguel; Wang, Kuan Wen; McAlpine, William; Ou, Feiya; Li, Xiaohong; Tang, Miao; Zang, Zhao; Wang, Jianhui; Hayse, Braden; Evers, Bret; Zhan, Xiaoming; Russell, Jamie L; Beutler, Bruce A.

In: Disease models & mechanisms, Vol. 11, No. 12, 18.12.2018.

Research output: Contribution to journalArticle

Turer, Emre E ; San Miguel, Miguel ; Wang, Kuan Wen ; McAlpine, William ; Ou, Feiya ; Li, Xiaohong ; Tang, Miao ; Zang, Zhao ; Wang, Jianhui ; Hayse, Braden ; Evers, Bret ; Zhan, Xiaoming ; Russell, Jamie L ; Beutler, Bruce A. / A viable hypomorphic Arnt2 mutation causes hyperphagic obesity, diabetes and hepatic steatosis. In: Disease models & mechanisms. 2018 ; Vol. 11, No. 12.
@article{4c343f556d994e1885c758057ee4d896,
title = "A viable hypomorphic Arnt2 mutation causes hyperphagic obesity, diabetes and hepatic steatosis",
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.",
keywords = "ENU, Hyperphagia, N-ethyl-N-nitrosourea, Obesity",
author = "Turer, {Emre E} and {San Miguel}, Miguel and Wang, {Kuan Wen} and William McAlpine and Feiya Ou and Xiaohong Li and Miao Tang and Zhao Zang and Jianhui Wang and Braden Hayse and Bret Evers and Xiaoming Zhan and Russell, {Jamie L} and Beutler, {Bruce A}",
year = "2018",
month = "12",
day = "18",
doi = "10.1242/dmm.035451",
language = "English (US)",
volume = "11",
journal = "DMM Disease Models and Mechanisms",
issn = "1754-8403",
publisher = "Company of Biologists Ltd",
number = "12",

}

TY - JOUR

T1 - A viable hypomorphic Arnt2 mutation causes hyperphagic obesity, diabetes and hepatic steatosis

AU - Turer, Emre E

AU - San Miguel, Miguel

AU - Wang, Kuan Wen

AU - McAlpine, William

AU - Ou, Feiya

AU - Li, Xiaohong

AU - Tang, Miao

AU - Zang, Zhao

AU - Wang, Jianhui

AU - Hayse, Braden

AU - Evers, Bret

AU - Zhan, Xiaoming

AU - Russell, Jamie L

AU - Beutler, Bruce A

PY - 2018/12/18

Y1 - 2018/12/18

N2 - 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.

AB - 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.

KW - ENU

KW - Hyperphagia

KW - N-ethyl-N-nitrosourea

KW - Obesity

UR - http://www.scopus.com/inward/record.url?scp=85058879196&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85058879196&partnerID=8YFLogxK

U2 - 10.1242/dmm.035451

DO - 10.1242/dmm.035451

M3 - Article

C2 - 30563851

AN - SCOPUS:85058879196

VL - 11

JO - DMM Disease Models and Mechanisms

JF - DMM Disease Models and Mechanisms

SN - 1754-8403

IS - 12

ER -