TBC1D1: A novel target in skeletal muscle for suppressing obesity and diabetes.
Final Report Abstract
In a positional cloning approach, we previously identified a loss-of-function mutation in Tbc1d1 as an obesity suppressor in the lean SJL mouse strain. Our data indicate that TBC1D1 is involved in glucose and lipid metabolism, and energy expenditure in skeletal muscle. The main objective of the research project was to validate whether TBC1D1 regulates whole body energy homeostasis and energy substrate preference and metabolism, and to investigate its role in GLUT4 translocation. For the experiments, several novel mouse models were established and characterized. Our results demonstrate that TBC1D1 constitutes a key player in regulating insulin and contraction-dependent glucose uptake, and fatty acid uptake and oxidation in skeletal muscle. Moreover, by analyzing an independently generated Tbc1d1-deficient mouse line, we showed that the loss-of-function mutation in the SJL-allele of Tbc1d1 is causal for the observed lean phenotype of the mice. With leptin-deficient mice lacking Tbc1d1 we could validate the role of the gene in regulating energy expenditure and body weight. Lastly, we generated and characterized mouse lines that lack either Tbc1d1, Tbc1d4 or both proteins. Our results allow for the first time dissection of the complex and tissue-specific functions of RabGAPs in insulin signalling.
Publications
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Animal Models in Diabetes Research. Springer 2012; 1-325
Joost, HG, Al-Hasani, H, Schürmann, A (Editors)
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The Rab-GTPase-activating protein TBC1D1 regulates skeletal muscle glucose metabolism. Am J Physiol Endocrinol Metab. 2012 Aug 15;303(4):E524-33
Szekeres F, Chadt A, Tom RZ, Deshmukh AS, Chibalin AV, Björnholm M, Al-Hasani H, Zierath JR
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Conventional knockout of Tbc1d1 in mice impairs insulin- and AICAR-stimulated glucose uptake in skeletal muscle. Endocrinology. 2013 Oct;154(10):3502-14
Dokas J, Chadt A, Nolden T, Himmelbauer H, Zierath JR, Joost HG, Al-Hasani H
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Deletion of both Rab-GTPase–activating proteins TBC1D1 and TBC1D4 in mice eliminates insulin- and AICAR-stimulated glucose transport. Diabetes. 2015 Mar;64(3):746-59
Chadt A, Immisch A, de Wendt C, Springer C, Zhou Z, Stermann T, Holman GD, Loffing- Cueni D, Loffing J, Joost HG, Al-Hasani H
