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  Comparative genomic analyses of multiple backcross mouse populations suggest SGCG as a novel potential obesity-modifier gene

Kuhn, T., Kaiser, K., Lebek, S., Altenhofen, D., Knebel, B., Herwig, R., et al. (2022). Comparative genomic analyses of multiple backcross mouse populations suggest SGCG as a novel potential obesity-modifier gene. Human Molecular Genetics, 2022: ddac150. doi:10.1093/hmg/ddac150.

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HumMolGenet_Kuhn et al_2022.pdf (Any fulltext), 1016KB
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Kuhn, Tanja, Author
Kaiser, Katharina, Author
Lebek, Sandra, Author
Altenhofen, Delsi , Author
Knebel, Birgit , Author
Herwig, Ralf1, Author           
Rasche, Axel1, Author           
Pelligra, Angela , Author
Görigk, Sarah , Author
Khuong, Jenny Minh-An , Author
Vogel, Heike, Author
Schürmann, Annette , Author
Blüher, Matthias , Author
Chadt, Alexandra , Author
Al-Hasani, Hadi , Author
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1Bioinformatics (Ralf Herwig), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_2385701              

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 Abstract: To nominate novel disease genes for obesity and type 2 diabetes (T2D), we recently generated two mouse backcross populations of the T2D-susceptible New Zealand Obese (NZO/HI) mouse strain and two genetically different, lean and T2D-resistant strains, 129P2/OlaHsd and C3HeB/FeJ. Comparative linkage analysis of our two female backcross populations identified seven novel body fat-associated quantitative trait loci (QTL). Only the locus Nbw14 (NZO body weight on chromosome 14) showed linkage to obesity-related traits in both backcross populations, indicating that the causal gene variant is likely specific for the NZO strain as NZO allele carriers in both crosses displayed elevated body weight and fat mass. To identify candidate genes for Nbw14, we used a combined approach of gene expression and haplotype analysis to filter for NZO-specific gene variants in gonadal white adipose tissue (gWAT), defined as the main QTL-target tissue. Only two genes, Arl11 and Sgcg, fulfilled our candidate criteria. In addition, expression QTL analysis revealed cis-signals for both genes within the Nbw14 locus. Moreover, retroviral overexpression of Sgcg in 3 T3-L1 adipocytes resulted in increased insulin-stimulated glucose uptake. In humans, mRNA levels of SGCG correlated with BMI and body fat mass exclusively in diabetic subjects, suggesting that SGCG may present a novel marker for metabolically unhealthy obesity. In conclusion, our comparative-cross analysis could substantially improve the mapping resolution of the obesity locus Nbw14. Future studies will shine light on the mechanism by which Sgcg may protect from the development of obesity.

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Language(s): eng - English
 Dates: 2022-05-102022-07-07
 Publication Status: Published online
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 Identifiers: DOI: 10.1093/hmg/ddac150
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Title: Human Molecular Genetics
Source Genre: Journal
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Publ. Info: Oxford, England : IRL Press
Pages: - Volume / Issue: 2022 Sequence Number: ddac150 Start / End Page: - Identifier: ISSN: 0964-6906
CoNE: https://pure.mpg.de/cone/journals/resource/954925581153