Department of Physiology/Metabolic Physiology, Institute of Neuroscience and Physiology, The Sahlgrenska Academy at University of Gothenburg, Medicinaregatan 11, SE-405 30 Göteborg, Sweden.
Department of Biomedical and Clinical Sciences, Linköping University, SE-58185 Linköping, Sweden.
Mol Metab. 2022 Sep;63:101535. doi: 10.1016/j.molmet.2022.101535. Epub 2022 Jun 24.
Sarco/endoplasmic reticulum Ca-ATPase (SERCA) transports Ca from the cytosol into the endoplasmic retitculum (ER) and is essential for appropriate regulation of intracellular Ca 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.
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 levels were recorded with dual-wavelength ratio imaging and mitochondrial function was assessed by Seahorse technology.
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 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.
Our data suggest causal links between reduced white adipocyte SERCA2 levels, deranged adipocyte Ca homeostasis, adipose tissue dysfunction and type-2 diabetes.
肌浆/内质网 Ca2+-ATP 酶（SERCA）将 Ca2+从细胞质转运到内质网（ER），对细胞内 Ca2+稳态的适当调节至关重要。本研究的目的是检验以下假设：SERCA 泵参与调节白色脂肪细胞激素分泌和脂肪组织功能的其他方面，而这种控制在肥胖诱导的 2 型糖尿病中受到干扰。
通过 Western blot 和 RT-qPCR 测量分离的人和小鼠脂肪细胞以及整个小鼠脂肪组织中的 SERCA 表达。为了测试 SERCA2 在脂肪细胞功能和全身代谢中的重要性，我们生成了脂肪细胞特异性 SERCA2 敲除小鼠。通过葡萄糖耐量和示踪研究、组织学分析、分离胰岛中葡萄糖刺激的胰岛素释放测量以及基因/蛋白质表达分析对小鼠进行代谢表型分析。我们还测试了药理学 SERCA 抑制和培养脂肪细胞中遗传 SERCA2 消融的作用。通过双波长比率成像记录细胞内和线粒体 Ca2+水平，并通过 Seahorse 技术评估线粒体功能。
我们证明，肥胖和 2 型糖尿病患者的白色脂肪细胞以及饮食诱导肥胖小鼠的脂肪细胞中，SERCA2 的表达下调。SERCA2 敲除的脂肪细胞表现出 Ca2+稳态紊乱，与内质网应激标志物上调和激素释放受损有关。这些脂肪细胞的改变与轻度脂肪营养不良、脂联素水平降低和葡萄糖耐量受损有关。有趣的是，脂肪细胞特异性 SERCA2 消融导致白色脂肪组织中葡萄糖摄取增加，而棕色脂肪组织中葡萄糖摄取减少。这种葡萄糖摄取的二分法效应归因于不同调节的线粒体功能。在白色脂肪细胞中，SERCA2 缺乏触发成纤维细胞生长因子 21（FGF21）的适应性增加、线粒体解偶联蛋白 1（UCP1）水平升高和耗氧量（OCR）增加。相比之下，与野生型对照相比，棕色 SERCA2 缺失的脂肪细胞显示 OCR 降低，尽管线粒体含量和 UCP1 水平增加。
我们的数据表明，白色脂肪细胞 SERCA2 水平降低、脂肪细胞 Ca2+稳态紊乱、脂肪组织功能障碍和 2 型糖尿病之间存在因果关系。
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