Gasser Marie, Lenglet Sébastien, Bararpour Nasim, Sajic Tatjana, Wiskott Kim, Augsburger Marc, Fracasso Tony, Gilardi Federica, Thomas Aurélien
Unit of Forensic Toxicology and Chemistry, CURML, Lausanne and Geneva University Hospitals, Lausanne, Geneva, Switzerland; Faculty Unit of Toxicology, CURML, Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.
Unit of Forensic Toxicology and Chemistry, CURML, Lausanne and Geneva University Hospitals, Lausanne, Geneva, Switzerland.
Toxicology. 2022 Mar 30;470:153153. doi: 10.1016/j.tox.2022.153153. Epub 2022 Mar 14.
Obesity is considered as a major public health concern with strong economic and social burdens. Exposure to pollutants such as heavy metals can contribute to the development of obesity and its associated metabolic disorders, including type 2 diabetes and cardiovascular diseases. Adipose tissue is an endocrine and paracrine organ that plays a key role in the development of these diseases and is one of the main target of heavy metal accumulation. In this study, we determined by inductively coupled plasma mass spectrometry cadmium concentrations in human subcutaneous and visceral adipose tissues, ranging between 2.5 nM and 2.5 µM. We found a positive correlation between cadmium levels and age, sex and smoking status and a negative correlation between cadmium and body mass index. Based on cadmium adipose tissue concentrations found in humans, we investigated the effects of cadmium exposure, at concentrations between 1 nM and 10 µM, on adipose-derived human mesenchymal stem cells differentiated into mature adipocytes in vitro. Transcriptomic analysis highlighted that such exposure altered the expression of genes involved in trace element homeostasis and heavy metal detoxification, such as Solute Carrier Family transporters and metallothioneins. This effect correlated with zinc level alteration in cells and cellular media. Interestingly, dysregulation of zinc homeostasis and transporters has been particularly associated with the development of obesity and type 2 diabetes. Moreover, we found that cadmium exposure induces the pro-inflammatory state of the adipocytes by enhancing the expression of genes such as IL-6, IL-1B and CCL2, cytokines also induced in obesity. Finally, cadmium modulates various adipocyte functions such as the insulin response signaling pathway and lipid homeostasis. Collectively, our data identified some of the cellular mechanisms by which cadmium alters adipocyte functions, thus highlighting new facets of its potential contribution to the progression of metabolic disorders.
肥胖被视为一个重大的公共卫生问题，会带来沉重的经济和社会负担。接触重金属等污染物会促使肥胖及其相关代谢紊乱的发展，包括2型糖尿病和心血管疾病。脂肪组织是一个内分泌和旁分泌器官，在这些疾病的发展中起关键作用，并且是重金属积累的主要靶点之一。在本研究中，我们通过电感耦合等离子体质谱法测定了人体皮下和内脏脂肪组织中的镉浓度，范围在2.5 nM至2.5 μM之间。我们发现镉水平与年龄、性别和吸烟状况呈正相关，与体重指数呈负相关。基于在人体中发现的镉脂肪组织浓度，我们研究了浓度在1 nM至10 μM之间的镉暴露对体外分化为成熟脂肪细胞的脂肪来源的人间充质干细胞的影响。转录组分析突出表明，这种暴露改变了参与微量元素稳态和重金属解毒的基因的表达，如溶质载体家族转运蛋白和金属硫蛋白。这种效应与细胞和细胞培养基中锌水平的改变相关。有趣的是，锌稳态和转运蛋白的失调尤其与肥胖和2型糖尿病的发展有关。此外，我们发现镉暴露通过增强IL-6、IL-1B和CCL2等基因的表达诱导脂肪细胞的促炎状态，这些细胞因子在肥胖中也会被诱导产生。最后，镉调节各种脂肪细胞功能，如胰岛素反应信号通路和脂质稳态。总体而言，我们的数据确定了镉改变脂肪细胞功能的一些细胞机制，从而突出了其对代谢紊乱进展潜在贡献的新方面。
