Mechanismen der durch physische Aktivität verursachten Verbesserungen der Glykämie in RabGAP-defizienten Mäusen
Zusammenfassung der Projektergebnisse
The Rab‐GTPase‐activating proteins (RabGAPs) TBC1D1 and AS160 are both key factors in the regulated trafficking of the insulin‐responsive glucose transporter GLUT4 from intracellular storage compartments to the plasma membrane. We and others previously demonstrated that depletion of one or both RabGAPs leads to disturbed insulin‐stimulated glucose transport into skeletal muscle and adipocytes, and, on the other hand, enhanced skeletal muscle lipid oxidation. In addition, the lack of either RabGAP in skeletal muscle results in impaired glucose uptake after stimulation of the muscle with the AMPK‐activator AICAR. The aim of this project was to assess the role of TBC1D1 and TBC1D4 in the contracting skeletal muscle both ex vivo and in vivo and to determine the specific tissue crosstalk that links RabGAP‐deficient skeletal muscle to whole‐body glycemia. By analysing a mouse model deficient in both RabGAPs and an inactive form of AMPK, we segregated the impact of either of the three factors in contraction‐mediated glucose uptake into skeletal muscle. We presented the small Rho‐GTPase Rac1 as additional factor in the RabGAP‐ and AMPK‐independent signal transmission of the contraction force. By subjecting global knockout mice for Tbc1d1 (D1KO), Tbc1d4 (D4KO) and both, Tbc1d1/4 (D1/4KO) to a chronic exercise training on treadmills, we demonstrated that D4KO and D1/4KO mice (but not D1KO mice) show profound improvements in glucose disposal and endurance capacity after the training intervention. Interestingly, the increased glucose clearance in trained mice was not facilitated by metabolic adaptations in the skeletal muscle from trained animals. In contrast, chronic treadmill training led to improvements in adipose tissue insulin sensitivity (Springer et al., manuscript in preparation). Next, we generated both inducible and conventional skeletal muscle‐ specific Tbc1d4‐knockout mice (mD4KO). Interestingly, the improvements in whole‐body and adipose tissue insulin sensitivity previously seen in the global D4KO and D1/4KO animals, respectively, was only partially present in the mD4KO mice. Therefore, we hypothesize that a deficiency in both tissues, skeletal muscle and white adipose tissue is necessary to promote full protection from Tbc1d4‐induced insulin resistance by chronic exercise training.
Projektbezogene Publikationen (Auswahl)
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AKT and AMP-activated protein kinase regulate TBC1D1 through phosphorylation and its interaction with the cytosolic tail of insulin-regulated aminopeptidase IRAP. Journal of Biological Chemistry, 293(46), 17853-17862.
Mafakheri, Samaneh; Flörke, Ralf R.; Kanngießer, Sibylle; Hartwig, Sonja; Espelage, Lena; De Wendt, Christian; Schönberger, Tina; Hamker, Nele; Lehr, Stefan; Chadt, Alexandra & Al-Hasani, Hadi
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Deletion of the RabGAP TBC1D1 Leads to Enhanced Insulin Secretion and Fatty Acid Oxidation in Islets From Male Mice. Endocrinology, 159(4), 1748-1761.
Stermann, Torben; Menzel, Franziska; Weidlich, Carmen; Jeruschke, Kay; Weiss, Jürgen; Altenhofen, Delsi; Benninghoff, Tim; Pujol, Anna; Bosch, Fatima; Rustenbeck, Ingo; Ouwens, D. Margriet; Thoresen, G. Hege; de Wendt, Christian; Lebek, Sandra; Schallschmidt, Tanja; Kragl, Martin; Lammert, Eckhard; Chadt, Alexandra & Al-Hasani, Hadi
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Impact of exercise on glucose homeostasis of different mouse models for impaired insulin sensitivity, Heinrich‐Heine‐Universität Düsseldorf, 2018
Christian Springer
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AMPK and TBC1D1 Regulate Muscle Glucose Uptake After, but Not During, Exercise and Contraction. Diabetes, 68(7), 1427-1440.
Kjøbsted, Rasmus; Roll, Julie L.W.; Jørgensen, Nicolas O.; Birk, Jesper B.; Foretz, Marc; Viollet, Benoit; Chadt, Alexandra; Al-Hasani, Hadi & Wojtaszewski, Jørgen F.P.
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Role of the RabGTPase‐activating proteins TBC1D1 and TBC1D4 in the regulation of skeletal muscle lipid metabolism, Heinrich‐Heine‐Universität Düsseldorf, 2019
Tim Benninghoff
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TBC1D4 Is Necessary for Enhancing Muscle Insulin Sensitivity in Response to AICAR and Contraction. Diabetes, 68(9), 1756-1766.
Kjøbsted, Rasmus; Chadt, Alexandra; Jørgensen, Nicolas O.; Kido, Kohei; Larsen, Jeppe K.; de Wendt, Christian; Al-Hasani, Hadi & Wojtaszewski, Jørgen F.P.
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RabGAPs in skeletal muscle function and exercise. Journal of Molecular Endocrinology, 64(1), R1-R19.
Espelage, Lena; Al-Hasani, Hadi & Chadt, Alexandra
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The RabGAPs TBC1D1 and TBC1D4 Control Uptake of Long-Chain Fatty Acids Into Skeletal Muscle via Fatty Acid Transporter SLC27A4/FATP4. Diabetes, 69(11), 2281-2293.
Benninghoff, Tim; Espelage, Lena; Eickelschulte, Samaneh; Zeinert, Isabel; Sinowenka, Isabelle; Müller, Frank; Schöndeling, Christina; Batchelor, Hannah; Cames, Sandra; Zhou, Zhou; Kotzka, Jörg; Chadt, Alexandra & Al-Hasani, Hadi
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AKT/AMPK-mediated phosphorylation of TBC1D4 disrupts the interaction with insulin-regulated aminopeptidase. Journal of Biological Chemistry, 296, 100637.
Eickelschulte, Samaneh; Hartwig, Sonja; Leiser, Ben; Lehr, Stefan; Joschko, Viola; Chokkalingam, Manopriya; Chadt, Alexandra & Al-Hasani, Hadi
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Contraction-Mediated Glucose Transport in Skeletal Muscle Is Regulated by a Framework of AMPK, TBC1D1/4, and Rac1. Diabetes, 70(12), 2796-2809.
de Wendt, Christian; Espelage, Lena; Eickelschulte, Samaneh; Springer, Christian; Toska, Laura; Scheel, Anna; Bedou, Awovi Didi; Benninghoff, Tim; Cames, Sandra; Stermann, Torben; Chadt, Alexandra & Al-Hasani, Hadi
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Physical activity attenuates postprandial hyperglycaemia in homozygous TBC1D4 loss-of-function mutation carriers. Diabetologia, 64(8), 1795-1804.
Schnurr, Theresia M.; Jørsboe, Emil; Chadt, Alexandra; Dahl-Petersen, Inger K.; Kristensen, Jonas M.; Wojtaszewski, Jørgen F. P.; Springer, Christian; Bjerregaard, Peter; Brage, Søren; Pedersen, Oluf; Moltke, Ida; Grarup, Niels; Al-Hasani, Hadi; Albrechtsen, Anders; Jørgensen, Marit E. & Hansen, Torben
