Adipocyte-specific ablation of the Ca 2+ pump SERCA2 impairs whole-body metabolic function and reveals the diverse metabolic flexibility of white and brown adipose tissue.
| Autor: | Bauzá-Thorbrügge M; Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Medicinaregatan 11, SE-405 30 Göteborg, Sweden. Electronic address: marcos.bauza.thorbrugge@gu.se., Banke E; Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Medicinaregatan 11, SE-405 30 Göteborg, Sweden. Electronic address: elin.banke@gmail.com., Chanclón B; Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Medicinaregatan 11, SE-405 30 Göteborg, Sweden. Electronic address: belenchanclon@gmail.com., Peris E; Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Medicinaregatan 11, SE-405 30 Göteborg, Sweden. Electronic address: eduard.peris@wlab.gu.se., Wu Y; Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Medicinaregatan 11, SE-405 30 Göteborg, Sweden. Electronic address: yanling.wu@neuro.gu.se., Musovic S; Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Medicinaregatan 11, SE-405 30 Göteborg, Sweden. Electronic address: saliha.musovic@gu.se., Jönsson C; Department of Biomedical and Clinical Sciences, Linköping University, SE-58185 Linköping, Sweden. Electronic address: cecilia.jonsson@liu.se., Strålfors P; Department of Biomedical and Clinical Sciences, Linköping University, SE-58185 Linköping, Sweden. Electronic address: peter.stralfors@liu.se., Rorsman P; Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Medicinaregatan 11, SE-405 30 Göteborg, Sweden; Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford OX4 7LE, UK. Electronic address: patrik.rorsman@hmc.ox.ac.uk., Olofsson CS; Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Medicinaregatan 11, SE-405 30 Göteborg, Sweden. Electronic address: charlotta.olofsson@gu.se., Wernstedt Asterholm I; Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Medicinaregatan 11, SE-405 30 Göteborg, Sweden. Electronic address: IWA@neuro.gu.se. |
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| Jazyk: | angličtina |
| Zdroj: | Molecular metabolism [Mol Metab] 2022 Sep; Vol. 63, pp. 101535. Date of Electronic Publication: 2022 Jun 24. |
| DOI: | 10.1016/j.molmet.2022.101535 |
| Abstrakt: | Objective: Sarco/endoplasmic reticulum Ca 2+ -ATPase (SERCA) transports Ca 2+ from the cytosol into the endoplasmic retitculum (ER) and is essential for appropriate regulation of intracellular Ca 2+ homeostasis. The objective of this study was to test the hypothesis that SERCA pumps are involved in the regulation of white adipocyte hormone secretion and other aspects of adipose tissue function and that this control is disturbed in obesity-induced type-2 diabetes. Methods: SERCA expression was measured in isolated human and mouse adipocytes as well as in whole mouse adipose tissue by Western blot and RT-qPCR. To test the significance of SERCA2 in adipocyte functionality and whole-body metabolism, we generated adipocyte-specific SERCA2 knockout mice. The mice were metabolically phenotyped by glucose tolerance and tracer studies, histological analyses, measurements of glucose-stimulated insulin release in isolated islets, and gene/protein expression analyses. We also tested the effect of pharmacological SERCA inhibition and genetic SERCA2 ablation in cultured adipocytes. Intracellular and mitochondrial Ca 2+ levels were recorded with dual-wavelength ratio imaging and mitochondrial function was assessed by Seahorse technology. Results: We demonstrate that SERCA2 is downregulated in white adipocytes from patients with obesity and type-2 diabetes as well as in adipocytes from diet-induced obese mice. SERCA2-ablated adipocytes display disturbed Ca 2+ homeostasis associated with upregulated ER stress markers and impaired hormone release. These adipocyte alterations are linked to mild lipodystrophy, reduced adiponectin levels, and impaired glucose tolerance. Interestingly, adipocyte-specific SERCA2 ablation leads to increased glucose uptake in white adipose tissue while the glucose uptake is reduced in brown adipose tissue. This dichotomous effect on glucose uptake is due to differently regulated mitochondrial function. In white adipocytes, SERCA2 deficiency triggers an adaptive increase in fibroblast growth factor 21 (FGF21), increased mitochondrial uncoupling protein 1 (UCP1) levels, and increased oxygen consumption rate (OCR). In contrast, brown SERCA2 null adipocytes display reduced OCR despite increased mitochondrial content and UCP1 levels compared to wild type controls. Conclusions: Our data suggest causal links between reduced white adipocyte SERCA2 levels, deranged adipocyte Ca 2+ homeostasis, adipose tissue dysfunction and type-2 diabetes. (Copyright © 2022 The Author(s). Published by Elsevier GmbH.. All rights reserved.) |
| Databáze: | MEDLINE |
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