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

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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Figure 1: The adiposity QTL Nob1 constitutes a diet-dependent obesity suppressor from the lean SJL strain.
Figure 2: Characterization of the crucial region of Nob1.
Figure 3: An SJL-specific deletion in exon 18 of Tbc1d1 results in premature termination of the protein and deletion of the TBC domain.
Figure 4: Relative expression of TBC1D1 in various tissues and cells.
Figure 5: TBC1D1 modulates fatty acid uptake and oxidation in cultured muscle cells.
Figure 6: Recombinant congenic B6.SJL-Nob1SJL/SJL mice show elevated fatty acid use and impaired glucose uptake in skeletal muscle.

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Acknowledgements

We thank C. Borchert, P. Großmann, A. Karasinsky, B. Rischke and T. Przewieslik for expert technical assistance; R. Herwig for the array analysis; and F. Rüschendorf for the linkage analysis. This work was supported in part by the German Bundesministerium für Bildung und Forschung (NGFN2, 01GS0487 and 01GR0472; PhysioSim, 0313325), the Deutsche Forschungsgemeinschaft (FOR441, Jo-117/11-2 and GRK-1208), the Swedish Research Council and the European Union (EUGENE2, LSHM-CT-2004-512013; SysProt, LSHG-CT-2006-37457).

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Correspondence to Hadi Al-Hasani.

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K.L., R.K., H.-G.J. and H.A. have filed a patent application (EP 07007072.7).

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Chadt, A., Leicht, K., Deshmukh, A. et al. Tbc1d1 mutation in lean mouse strain confers leanness and protects from diet-induced obesity. Nat Genet 40, 1354–1359 (2008). https://doi.org/10.1038/ng.244

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