Tbc1d1 mutation in lean mouse strain confers leanness and protects from 
diet-induced obesity

Chadt, Alexandra; Leicht, Katja; Deshmukh, Atul; Jiang, Lake Q.; Scherneck, Stephan; Bernhardt, Ulrike; Dreja, Tanja; Vogel, Heike; Schmolz, Katja; Kluge, Reinhart; Zierath, Juleen R.; Hultschig, Claus; Hoeben, Rob C.; Schürmann, Annette; Joost, Hans-Georg; Al-Hasani, Hadi

doi:10.1038/ng.244

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Tbc1d1 mutation in lean mouse strain confers leanness and protects from diet-induced obesity

Chadt, A., Leicht, K., Deshmukh, A., Jiang, L. Q., Scherneck, S., Bernhardt, U., et al. (2008). Tbc1d1 mutation in lean mouse strain confers leanness and protects from diet-induced obesity. Nature Genetics, 40(11), 1354-1359. doi:10.1038/ng.244.

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Item Permalink: https://hdl.handle.net/11858/00-001M-0000-0010-7ED7-9 Version Permalink: https://hdl.handle.net/11858/00-001M-0000-0010-7ED8-7

Genre: Journal Article

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Chadt, Alexandra, Author
Leicht, Katja, Author
Deshmukh, Atul, Author
Jiang, Lake Q., Author
Scherneck, Stephan, Author
Bernhardt, Ulrike, Author
Dreja, Tanja, Author
Vogel, Heike, Author
Schmolz, Katja, Author
Kluge, Reinhart, Author
Zierath, Juleen R., Author
Hultschig, Claus¹, Author
Hoeben, Rob C., Author
Schürmann, Annette, Author
Joost, Hans-Georg, Author
Al-Hasani, Hadi, Author

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1Max Planck Society, ou_persistent13

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Abstract: We previously identified Nob1 as a quantitative trait locus for high-fat diet–induced obesity and diabetes in genome-wide scans of outcross populations of obese and lean mouse strains. Additional crossbreeding experiments indicated that Nob1 represents an obesity suppressor from the lean Swiss Jim Lambert (SJL) strain. Here we identify a SJL-specific mutation in the Tbc1d1 gene that results in a truncated protein lacking the TBC Rab–GTPase-activating protein domain. TBC1D1, which has been recently linked to human obesity, is related to the insulin signaling protein AS160 and is predominantly expressed in skeletal muscle. Knockdown of TBC1D1 in skeletal muscle cells increased fatty acid uptake and oxidation, whereas overexpression of TBC1D1 had the opposite effect. Recombinant congenic mice lacking TBC1D1 showed reduced body weight, decreased respiratory quotient, increased fatty acid oxidation and reduced glucose uptake in isolated skeletal muscle. Our data strongly suggest that mutation of Tbc1d1 suppresses high-fat diet–induced obesity by increasing lipid use in skeletal muscle.

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Language(s): eng - English

Dates: Date issued: 2008-10-19

Publication Status: Issued

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Identifiers: eDoc: 406824
DOI: 10.1038/ng.244
URI: http://www.nature.com/ng/journal/v40/n11/pdf/ng.244.pdf

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Title: Nature Genetics

Source Genre: Journal

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Pages: - Volume / Issue: 40 (11) Sequence Number: - Start / End Page: 1354 - 1359 Identifier: ISSN: 1061-4036