Adipocyte-specific ablation of the Ca2+ pump SERCA2 impairs whole-body metabolic function and reveals the diverse metabolic flexibility of white and brown adipose tissue

Marco Bauzá-Thorbrügge; Elin Banke; Belén Chanclón; Eduard Peris; Yanling Wu; Saliha Musovic; Cecilia Jönsson; Peter Strålfors; Patrik Rorsman; Charlotta S. Olofsson; Ingrid Wernstedt Asterholm

Molecular Metabolism (Sep 2022)

Adipocyte-specific ablation of the Ca2+ pump SERCA2 impairs whole-body metabolic function and reveals the diverse metabolic flexibility of white and brown adipose tissue

Marco Bauzá-Thorbrügge,
Elin Banke,
Belén Chanclón,
Eduard Peris,
Yanling Wu,
Saliha Musovic,
Cecilia Jönsson,
Peter Strålfors,
Patrik Rorsman,
Charlotta S. Olofsson,
Ingrid Wernstedt Asterholm

Affiliations

Marco Bauzá-Thorbrügge: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Medicinaregatan 11, SE-405 30 Göteborg, Sweden
Elin Banke: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Medicinaregatan 11, SE-405 30 Göteborg, Sweden
Belén Chanclón: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Medicinaregatan 11, SE-405 30 Göteborg, Sweden
Eduard Peris: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Medicinaregatan 11, SE-405 30 Göteborg, Sweden
Yanling Wu: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Medicinaregatan 11, SE-405 30 Göteborg, Sweden
Saliha Musovic: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Medicinaregatan 11, SE-405 30 Göteborg, Sweden
Cecilia Jönsson: Department of Biomedical and Clinical Sciences, Linköping University, SE-58185 Linköping, Sweden
Peter Strålfors: Department of Biomedical and Clinical Sciences, Linköping University, SE-58185 Linköping, Sweden
Patrik Rorsman: 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
Charlotta S. Olofsson: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Medicinaregatan 11, SE-405 30 Göteborg, Sweden; Corresponding author. University of Gothenburg, The Sahlgrenska Academy, Dept. Neuroscience and Physiology, Section of Metabolic Physiology, Box 432, SE-405 30 Göteborg, Sweden.
Ingrid Wernstedt Asterholm: Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Medicinaregatan 11, SE-405 30 Göteborg, Sweden; Corresponding author. University of Gothenburg, The Sahlgrenska Academy, Dept. Neuroscience and Physiology, Section of Metabolic Physiology, Box 432, SE-405 30 Göteborg, Sweden.

Journal volume & issue: Vol. 63
p. 101535

Abstract

Read online

Objective: Sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) transports Ca2+ from the cytosol into the endoplasmic retitculum (ER) and is essential for appropriate regulation of intracellular Ca2+ 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 Ca2+ 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 Ca2+ 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 Ca2+ homeostasis, adipose tissue dysfunction and type-2 diabetes.

Published in Molecular Metabolism

ISSN: 2212-8778 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Medicine: Internal medicine
Website: https://www.journals.elsevier.com/molecular-metabolism/

About the journal

Abstract

Keywords