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  • Original Article
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Animal Models

Tbc1d1 deletion suppresses obesity in leptin-deficient mice

International Journal of Obesity volume 40, pages 1242–1249 (2016)Cite this article

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Abstract

Background:

Variants in the gene TBC1D1 have been previously associated with obesity-related traits in several species, including humans, mice, rabbits and chicken. While in humans variants in TBC1D1 were linked to obesity, disruption of the Tbc1d1 gene reduced body weight in mice. TBC1D1 has been identified as a regulator of insulin-dependent glucose transport in skeletal muscle, however, its role in energy homeostasis in the obese state remains unclear. The impact of TBC1D1 deficiency on energy homeostasis, glucose and lipid metabolism in an established mouse model of obesity was examined.

Methods:

Obese leptin (ob/ob)- and Tbc1d1-double-deficient mice (D1KO-ob/ob) were generated by crossing obese B6.V.Lepob/ob-mice with lean Tbc1d1-deficient mice on a C57BL/6J background. Male mice on either standard (SD) or high-fat diet (HFD) were analyzed for body weight, body composition, food intake, voluntary physical activity and energy expenditure by indirect calorimetry. Glucose and insulin tolerance as well as glucose transport and fatty acid oxidation in skeletal muscle were analyzed.

Results:

In obese mice, Tbc1d1 deficiency resulted in reduced body weight on both SD and HFD. However, food intake was unchanged on SD or even increased in HFD-fed Tbc1d1-deficient mice without alterations in voluntary physical activity. Despite substantially reduced insulin-stimulated glucose transport and increased fatty acid oxidation in intact isolated skeletal muscle, obese Tbc1d1-deficient mice showed no gross changes in glycemia and glucose tolerance compared with obese controls. Indirect calorimetry revealed that obese Tbc1d1-deficient mice had a decreased respiratory quotient together with increased daily energy expenditure.

Conclusions:

In obese leptin-deficient mice, lack of TBC1D1 has no impact on feeding behavior or energy intake but results in increased energy expenditure, altered energy substrate preference with increased fatty acid oxidation and suppression of obesity. TBC1D1 may have an evolutionary conserved role in regulating energy homeostasis in vertebrates.

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References

  1. Richardson PM, Zon LI . Molecular cloning of a cDNA with a novel domain present in the tre-2 oncogene and the yeast cell cycle regulators BUB2 and cdc16. Oncogene 1995; 11: 1139–1148.

    CAS  PubMed  Google Scholar 

  2. Roach WG, Chavez JA, Miinea CP, Lienhard GE . Substrate specificity and effect on GLUT4 translocation of the Rab GTPase-activating protein Tbc1d1. Biochem J 2007; 403: 353–358.

    Article  CAS  Google Scholar 

  3. Sano H, Kane S, Sano E, Miinea CP, Asara JM, Lane WS et al. Insulin-stimulated phosphorylation of a Rab GTPase-activating protein regulates GLUT4 translocation. J Biol Chem 2003; 278: 14599–14602.

    Article  CAS  Google Scholar 

  4. An D, Toyoda T, Taylor EB, Yu H, Fujii N, Hirshman MF et al. TBC1D1 regulates insulin- and contraction-induced glucose transport in mouse skeletal muscle. Diabetes 2010; 59: 1358–1365.

    Article  CAS  Google Scholar 

  5. Vichaiwong K, Purohit S, An D, Toyoda T, Jessen N, Hirshman MF et al. Contraction regulates site-specific phosphorylation of TBC1D1 in skeletal muscle. Biochem J 2010; 431: 311–320.

    Article  CAS  Google Scholar 

  6. Chadt A, Leicht K, Deshmukh A, Jiang LQ, Scherneck S, Bernhardt U et al. Tbc1d1 mutation in lean mouse strain confers leanness and protects from diet-induced obesity. Nat Genet 2008; 40: 1354–1359.

    Article  CAS  Google Scholar 

  7. Dokas J, Chadt A, Nolden T, Himmelbauer H, Zierath JR, Joost HG et al. Conventional knockout of Tbc1d1 in mice impairs insulin- and AICAR-stimulated glucose uptake in skeletal muscle. Endocrinology 2013; 154: 3502–3514.

    Article  CAS  Google Scholar 

  8. Szekeres F, Chadt A, Tom RZ, Deshmukh AS, Chibalin AV, Bjornholm M et al. The Rab-GTPase-activating protein TBC1D1 regulates skeletal muscle glucose metabolism. Am J Physiol Endocrinol Metab 2012; 303: E524–E533.

    Article  CAS  Google Scholar 

  9. Chadt A, Immisch A, de Wendt C, Springer C, Zhou Z, Stermann T et al. Deletion of both Rab-GTPase-activating proteins TBC1D1 and TBC1D4 in mice eliminates insulin- and AICAR-stimulated glucose transport. Diabetes 2015; 64: 746–759.

    Article  CAS  Google Scholar 

  10. Stone S, Abkevich V, Russell DL, Riley R, Timms K, Tran T et al. TBC1D1 is a candidate for a severe obesity gene and evidence for a gene/gene interaction in obesity predisposition. Hum Mol Genet 2006; 15: 2709–2720.

    Article  CAS  Google Scholar 

  11. Meyre D, Farge M, Lecoeur C, Proenca C, Durand E, Allegaert F et al. R125W coding variant in TBC1D1 confers risk for familial obesity and contributes to linkage on chromosome 4p14 in the French population. Hum Mol Genet 2008; 17: 1798–1802.

    Article  CAS  Google Scholar 

  12. Fontanesi L, Colombo M, Tognazzi L, Scotti E, Buttazzoni L, Dall'Olio S et al. The porcine TBC1D1 gene: mapping, SNP identification, and association study with meat, carcass and production traits in Italian heavy pigs. Mol Biol Rep 2011; 38: 1425–1431.

    Article  CAS  Google Scholar 

  13. Yang ZJ, Fu L, Zhang GW, Yang Y, Chen SY, Wang J et al. Identification and association of SNPs in TBC1D1 gene with growth traits in two rabbit breeds. Asian-Australas J Anim Sci 2013; 26: 1529–1535.

    Article  CAS  Google Scholar 

  14. Wang Y, Xu HY, Gilbert ER, Peng X, Zhao XL, Liu YP et al. Detection of SNPs in the TBC1D1 gene and their association with carcass traits in chicken. Gene 2014; 547: 288–294.

    Article  CAS  Google Scholar 

  15. Nassar MK, Goraga ZS, Brockmann GA . Quantitative trait loci segregating in crosses between New Hampshire and White Leghorn chicken lines: IV. Growth performance. Anim Genet 2015; 46: 441–446.

    Article  CAS  Google Scholar 

  16. Livak KJ, Schmittgen TD . Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 2001; 25: 402–408.

    Article  CAS  Google Scholar 

  17. Hargett SR, Walker NN, Hussain SS, Hoehn KL, Keller SR . Deletion of the Rab GAP Tbc1d1 modifies glucose, lipid, and energy homeostasis in mice. Am J Physiol Endocrinol Metab 2015; 309: E233–E245.

    Article  CAS  Google Scholar 

  18. Stockli J, Meoli CC, Hoffman NJ, Fazakerley DJ, Pant H, Cleasby ME et al. The RabGAP TBC1D1 plays a central role in exercise-regulated glucose metabolism in skeletal muscle. Diabetes 2015; 64: 1914–1922.

    Article  CAS  Google Scholar 

  19. Tschop MH, Speakman JR, Arch JR, Auwerx J, Bruning JC, Chan L et al. A guide to analysis of mouse energy metabolism. Nat Methods 2012; 9: 57–63.

    Article  Google Scholar 

  20. Maher AC, McFarlan J, Lally J, Snook LA, Bonen A . TBC1D1 reduces palmitate oxidation by inhibiting beta-HAD activity in skeletal muscle. Am J Physiol Regul Integr Comp Physiol 2014; 307: R1115–R1123.

    Article  CAS  Google Scholar 

  21. Abu-Elheiga L, Matzuk MM, Abo-Hashema KA, Wakil SJ . Continuous fatty acid oxidation and reduced fat storage in mice lacking acetyl-CoA carboxylase 2. Science 2001; 291: 2613–2616.

    Article  CAS  Google Scholar 

  22. Choi CS, Savage DB, Abu-Elheiga L, Liu ZX, Kim S, Kulkarni A et al. Continuous fat oxidation in acetyl-CoA carboxylase 2 knockout mice increases total energy expenditure, reduces fat mass, and improves insulin sensitivity. Proc Natl Acad Sci USA 2007; 104: 16480–16485.

    Article  CAS  Google Scholar 

  23. Hoehn KL, Turner N, Swarbrick MM, Wilks D, Preston E, Phua Y et al. Acute or chronic upregulation of mitochondrial fatty acid oxidation has no net effect on whole-body energy expenditure or adiposity. Cell Metab 2010; 11: 70–76.

    Article  CAS  Google Scholar 

  24. Kahn BB, Flier JS . Obesity and insulin resistance. J Clin Invest 2000; 106: 473–481.

    Article  CAS  Google Scholar 

  25. Knuppel S, Rohde K, Meidtner K, Drogan D, Holzhutter HG, Boeing H et al. Evaluation of 41 candidate gene variants for obesity in the EPIC-Potsdam cohort by multi-locus stepwise regression. PLoS One 2013; 8: e68941.

    Article  Google Scholar 

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Acknowledgements

We thank Carolin Borchert, Viviane Hass, Anne Karasinsky, Stephanie Sartig and Diana Schulze for expert technical assistance. This work was supported by the Ministry of Science and Research of the State of North Rhine-Westphalia (MIWF NRW) and the German Federal Ministry of Health (BMG) and was funded in part by grants from the Deutsche Forschungsgemeinschaft (GRK1208, AL452/4-1), and the EFSD/Lilly European Diabetes Research Program.

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Author notes

  1. J Dokas

    Present address: 4Present address: Institute of Laboratory Medicine, Clinical Chemistry and Molecular Diagnostics, University Hospital Leipzig, Leipzig, Germany.,

Authors and Affiliations

  1. German Institute for Human Nutrition, Potsdam, Germany

    J Dokas & H-G Joost

  2. German Diabetes Center, Leibniz Center for Diabetes Research at the Heinrich Heine University Düsseldorf, Düsseldorf, Germany

    A Chadt & H Al-Hasani

  3. German Center for Diabetes Research (DZD), München-Neuherberg, Germany,

    A Chadt, H-G Joost & H Al-Hasani

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  1. J Dokas
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Correspondence to H Al-Hasani.

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Dokas, J., Chadt, A., Joost, HG. et al. Tbc1d1 deletion suppresses obesity in leptin-deficient mice. Int J Obes 40, 1242–1249 (2016). https://doi.org/10.1038/ijo.2016.45

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