Identification of mutations through dominant screening for obesity using C57BL/6 substrains

Mohammad Sarowar Hossain, Fuyuki Asano, Tomoyuki Fujiyama, Chika Miyoshi, Makito Sato, Aya Ikkyu, Satomi Kanno, Noriko Hotta, Miyo Kakizaki, Takato Honda, Staci J. Kim, Haruna Komiya, Ikuo Miura, Tomohiro Suzuki, Kimio Kobayashi, Hideki Kaneda, Vivek Kumar, Joseph S Takahashi, Shigeharu Wakana, Hiromasa Funato & 1 others Masashi Yanagisawa

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The discovery of leptin substantiated the usefulness of a forward genetic approach in elucidating the molecular network regulating energy metabolism. However, no successful dominant screening for obesity has been reported, which may be due to the influence of quantitative trait loci between the screening and counter strains and the low fertility of obese mice. Here, we performed a dominant screening for obesity using C57BL/6 substrains, C57BL/6J and C57BL/6N, with the routine use of in vitro fertilization. The screening of more than 5000 mutagenized mice established two obese pedigrees in which single nucleotide substitutions in Mc4r and Sim1 genes were identified through whole-exome sequencing. The mutation in the Mc4r gene produces a premature stop codon, and the mutant SIM1 protein lacks transcriptional activity, showing that the haploinsufficiency of SIM1 and MC4R results in obesity. We further examined the hypothalamic neuropeptide expressions in the mutant pedigrees and mice with diet-induced obesity, which showed that each obesity mouse model has distinct neuropeptide expression profiles. This forward genetic screening scheme is useful and applicable to any research field in which mouse models work.

Original languageEnglish (US)
Article number32453
JournalScientific Reports
Volume6
DOIs
StatePublished - Sep 2 2016

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Obesity
Mutation
Pedigree
Neuropeptides
Exome
Haploinsufficiency
Obese Mice
Nonsense Codon
Quantitative Trait Loci
Genetic Testing
Mutant Proteins
Fertilization in Vitro
Leptin
Energy Metabolism
Genes
Fertility
Nucleotides
Diet
Research

ASJC Scopus subject areas

  • General

Cite this

Identification of mutations through dominant screening for obesity using C57BL/6 substrains. / Hossain, Mohammad Sarowar; Asano, Fuyuki; Fujiyama, Tomoyuki; Miyoshi, Chika; Sato, Makito; Ikkyu, Aya; Kanno, Satomi; Hotta, Noriko; Kakizaki, Miyo; Honda, Takato; Kim, Staci J.; Komiya, Haruna; Miura, Ikuo; Suzuki, Tomohiro; Kobayashi, Kimio; Kaneda, Hideki; Kumar, Vivek; Takahashi, Joseph S; Wakana, Shigeharu; Funato, Hiromasa; Yanagisawa, Masashi.

In: Scientific Reports, Vol. 6, 32453, 02.09.2016.

Research output: Contribution to journalArticle

Hossain, MS, Asano, F, Fujiyama, T, Miyoshi, C, Sato, M, Ikkyu, A, Kanno, S, Hotta, N, Kakizaki, M, Honda, T, Kim, SJ, Komiya, H, Miura, I, Suzuki, T, Kobayashi, K, Kaneda, H, Kumar, V, Takahashi, JS, Wakana, S, Funato, H & Yanagisawa, M 2016, 'Identification of mutations through dominant screening for obesity using C57BL/6 substrains', Scientific Reports, vol. 6, 32453. https://doi.org/10.1038/srep32453
Hossain, Mohammad Sarowar ; Asano, Fuyuki ; Fujiyama, Tomoyuki ; Miyoshi, Chika ; Sato, Makito ; Ikkyu, Aya ; Kanno, Satomi ; Hotta, Noriko ; Kakizaki, Miyo ; Honda, Takato ; Kim, Staci J. ; Komiya, Haruna ; Miura, Ikuo ; Suzuki, Tomohiro ; Kobayashi, Kimio ; Kaneda, Hideki ; Kumar, Vivek ; Takahashi, Joseph S ; Wakana, Shigeharu ; Funato, Hiromasa ; Yanagisawa, Masashi. / Identification of mutations through dominant screening for obesity using C57BL/6 substrains. In: Scientific Reports. 2016 ; Vol. 6.
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