Inhibition of mitochondrial complex 1 by the S6K1 inhibitor PF-4708671 partly contributes to its glucose metabolic effects in muscle and liver cells
| Autor: | Benoit Viollet, Michael Shum, Philippe St-Pierre, André Marette, Vanessa P. Houde, Marc Foretz, Rafael Junges Moreira, Vicky Bellemare, Kerstin Bellmann |
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| Přispěvatelé: | Axe Cardiologie [Québec, Canada], Quebec Heart and Lung Research Institute (IUCPQ), Department of Medicine [Hamilton, ON, Canada], McMaster University [Hamilton, Ontario], Institut Interdisciplinaire d'Innovation Technologique [Sherbrooke] (3IT), Université de Sherbrooke (UdeS), Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Institute of Nutraceuticals and Functional Foods (INAF), Université Laval [Québec] (ULaval), Institut Interdisciplinaire d'Innovation Technologique (3IT), Université de Sherbrooke [Sherbrooke], Université Laval |
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
PF-4708671 obesity Glucose uptake medicine.medical_treatment mTORC1 AMP-Activated Protein Kinases Biochemistry Piperazines Mice Insulin Glucose homeostasis Phosphorylation Mice Knockout diabetes Chemistry Imidazoles Ribosomal Protein S6 Kinases 70-kDa hepatic glucose production S6K1 [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism Mitochondria [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biomolecules [q-bio.BM] Liver AMPK-activated protein kinase (AMPK) mitochondrial complex I medicine.medical_specialty glucose metabolism P70-S6 Kinase 1 Carbohydrate metabolism Ribosomal Protein S6 Kinases 90-kDa Cell Line 03 medical and health sciences Insulin resistance mechanistic target of rapamycin (mTOR) Internal medicine medicine Animals glucose homeostasis [SDV.BBM.BC]Life Sciences [q-bio]/Biochemistry Molecular Biology/Biochemistry [q-bio.BM] Muscle Skeletal Molecular Biology Electron Transport Complex I 030102 biochemistry & molecular biology AMPK [SDV.BBM.BM]Life Sciences [q-bio]/Biochemistry Molecular Biology/Molecular biology Cell Biology medicine.disease Rats glucose uptake Mice Inbred C57BL p70 S6 kinase (S6K1) Metabolism Glucose 030104 developmental biology Endocrinology gluconeogenesis |
| Zdroj: | Journal of Biological Chemistry Journal of Biological Chemistry, American Society for Biochemistry and Molecular Biology, 2019, 294 (32), pp.12250-12260. ⟨10.1074/jbc.RA119.008488⟩ J Biol Chem |
| ISSN: | 0021-9258 1083-351X |
| Popis: | International audience; mTOR complex 1 (mTORC1) and p70 S6 kinase (S6K1) are both involved in the development of obesity-linked insulin resistance. Recently, we showed that the S6K1 inhibitor PF-4708671 (PF) increases insulin sensitivity. However, we also reported that PF can increase glucose metabolism even in the absence of insulin in muscle and hepatic cells. Here we further explored the potential mechanisms by which PF increases glucose metabolism in muscle and liver cells independent of insulin. Time course experiments revealed that PF induces AMP-activated protein kinase (AMPK) activation before inhibiting S6K1. However, PF-induced glucose uptake was not prevented in primary muscle cells from AMPK α1/2 double KO (dKO) mice. Moreover, PF-mediated suppression of hepatic glucose production was maintained in hepatocytes derived from AMPK α1/2-dKO mice. Remarkably, PF could still reduce glucose production and activate AMPK in hepatocytes from S6K1/2 dKO mice. Mechanistically, bioenergetics experiments revealed that PF reduces mitochondrial complex I activity in both muscle and hepatic cells. The stimulatory effect of PF on glucose uptake was partially reduced by expression of the Saccharomyces cerevisiae NADH:ubiquinone oxidoreductase in L6 cells. These results indicate that PF-mediated S6K1 inhibition is not required for its effect on insulin-independent glucose metabolism and AMPK activation. We conclude that, although PF rapidly activates AMPK, its ability to acutely increase glucose uptake and suppress glucose production does not require AMPK activation. Unexpectedly, PF rapidly inhibits mitochondrial complex I activity, a mechanism that partially underlies PF's effect on glucose metabolism. |
| Databáze: | OpenAIRE |
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