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

Abstract

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.

Graphical abstract

Highlights

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  Adipocyte SERCA2 is downregulated in human subjects with type-2 diabetes.

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  Loss of SERCA2 disturbs the intracellular Ca ²⁺ homeostasis in adipocytes.

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  Impaired metabolism and altered adipokine levels in adipocyte-SERCA2 null mice.

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  Loss of SERCA2 accelerates metabolic processes in white adipocytes.

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  Loss of SERCA2 impairs the mitochondrial function of brown adipocytes.