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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
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 i...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9287368/ https://www.ncbi.nlm.nih.gov/pubmed/35760318 http://dx.doi.org/10.1016/j.molmet.2022.101535 |
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author | Bauzá-Thorbrügge, Marco Banke, Elin Chanclón, Belén Peris, Eduard Wu, Yanling Musovic, Saliha Jönsson, Cecilia Strålfors, Peter Rorsman, Patrik Olofsson, Charlotta S. Wernstedt Asterholm, Ingrid |
author_facet | Bauzá-Thorbrügge, Marco Banke, Elin Chanclón, Belén Peris, Eduard Wu, Yanling Musovic, Saliha Jönsson, Cecilia Strålfors, Peter Rorsman, Patrik Olofsson, Charlotta S. Wernstedt Asterholm, Ingrid |
author_sort | Bauzá-Thorbrügge, Marco |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9287368 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-92873682022-07-17 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 Bauzá-Thorbrügge, Marco Banke, Elin Chanclón, Belén Peris, Eduard Wu, Yanling Musovic, Saliha Jönsson, Cecilia Strålfors, Peter Rorsman, Patrik Olofsson, Charlotta S. Wernstedt Asterholm, Ingrid Mol Metab Original Article 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. Elsevier 2022-06-24 /pmc/articles/PMC9287368/ /pubmed/35760318 http://dx.doi.org/10.1016/j.molmet.2022.101535 Text en © 2022 The Author(s) https://creativecommons.org/licenses/by/4.0/This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Original Article Bauzá-Thorbrügge, Marco Banke, Elin Chanclón, Belén Peris, Eduard Wu, Yanling Musovic, Saliha Jönsson, Cecilia Strålfors, Peter Rorsman, Patrik Olofsson, Charlotta S. Wernstedt Asterholm, Ingrid 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 |
title | 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 |
title_full | 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 |
title_fullStr | 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 |
title_full_unstemmed | 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 |
title_short | 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 |
title_sort | 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 |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9287368/ https://www.ncbi.nlm.nih.gov/pubmed/35760318 http://dx.doi.org/10.1016/j.molmet.2022.101535 |
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