Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010), 17190 Salt, Spain; CIBER de la Fisiopatología de la Obesidad y Nutrición (CIBEROBN) and Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain.
Department of Diabetes, Endocrinology and Nutrition, Institut d'Investigació Biomèdica de Girona (IdIBGi), CIBEROBN (CB06/03/010), 17190 Salt, Spain; CIBER de la Fisiopatología de la Obesidad y Nutrición (CIBEROBN) and Instituto de Salud Carlos III (ISCIII), 28029 Madrid, Spain; Department of Medical Sciences, School of Medicine, University of Girona, 17071 Girona, Spain.
EBioMedicine. 2022 Nov;85:104302. doi: 10.1016/j.ebiom.2022.104302. Epub 2022 Oct 4.
Adipose tissue is a source of multiple factors that modulate systemic insulin sensitivity and cardiovascular risk. Taurine is obtained from the diet but it is less known that it is endogenously synthesized by cysteine dioxygenase type 1 (CDO1). CDO1 exerts a role in adipose tissue from rodent models, but the potential translational value in humans is not available in the literature.
CDO1 gene expression was analysed in visceral and subcutaneous adipose tissue samples in association with metabolic traits in participants with different degrees of obesity in four independent cohorts. CDO1 was also evaluated in isolated human adipocytes in vitro. Mechanistically, CDO1gene knockdown (KD) of human preadipocytes and adipose-derived mesenchymal stem cells (ASC52telo) (using lentiviral particles) was also evaluated. Mitochondrial respiratory function of adipocytes was evaluated using Seahorse.
Both visceral (VAT) and subcutaneous adipose tissue (SAT) CDO1 mRNA was associated with gene expression markers of adipose tissue function in the four cohorts. Higher CDO1 expression was linked to decreased fasting triglycerides and blood HbA1c even after adjusting by age, BMI and sex. In addition, CDO1 mRNA positively correlated with the expression of genes involved in adipogenesis and negatively with different inflammatory markers. Both VAT and SAT CDO1 mRNA was mainly expressed in adipocytes and significantly increased during adipocyte differentiation, but attenuated under inflammatory conditions. Mechanistically, CDO1 gene KD reduced taurine biosynthesis, evidencing lower CDO1 activity. In both human preadipocytes and ASC52telo cells, CDO1 gene KD resulted in decreased gene expression markers of adipogenesis (ADIPOQ, FABP4, FASN, SLC2A4, CEBPA) and increased inflammatory genes (TNF and IL6) during adipocyte differentiation. Of note, CDO1 gene KD led to decreased mitochondrial respiratory function in parallel to decreased expression of mitochondrial function-, but not biogenesis-related genes.
Current findings show the relevance of CDO1 in adipose tissue physiology, suggesting its contribution to an improved systemic metabolic profile.
This work was partially supported by research grants PI16/01173, PI19/01712, PI20/01090 and PI21/01361 from the Instituto de Salud Carlos III from Spain, Fondo Europeo de Desarrollo Regional (FEDER) funds, and VII Spanish Diabetes Association grants to Basic Diabetes Research Projects led by young researchers.
脂肪组织是调节全身胰岛素敏感性和心血管风险的多种因素的来源。牛磺酸可从饮食中获得，但人们较少知道它是由半胱氨酸双加氧酶 1 型 (CDO1) 内源性合成的。CDO1 在啮齿动物模型的脂肪组织中发挥作用，但在文献中尚未发现其在人类中的潜在转化价值。
在四个独立的队列中，根据不同程度肥胖的参与者的代谢特征，分析内脏和皮下脂肪组织样本中的 CDO1 基因表达。还在体外分离的人脂肪细胞中评估了 CDO1。从机制上讲，还评估了人前脂肪细胞和脂肪衍生间充质干细胞 (ASC52telo) 的 CDO1 基因敲低 (KD)（使用慢病毒颗粒）。使用 Seahorse 评估脂肪细胞的线粒体呼吸功能。
四个队列中，内脏 (VAT) 和皮下脂肪组织 (SAT) 的 CDO1 mRNA 均与脂肪组织功能的基因表达标志物相关。较高的 CDO1 表达与空腹甘油三酯降低和血液 HbA1c 降低相关，即使在调整年龄、BMI 和性别后也是如此。此外，CDO1 mRNA 与参与脂肪生成的基因表达呈正相关，与不同的炎症标志物呈负相关。VAT 和 SAT 的 CDO1 mRNA 主要在脂肪细胞中表达，并在脂肪细胞分化过程中显著增加，但在炎症条件下减少。从机制上讲，CDO1 基因 KD 降低了牛磺酸生物合成，表明 CDO1 活性降低。在人前脂肪细胞和 ASC52telo 细胞中，CDO1 基因 KD 导致脂肪生成的基因表达标志物减少（ADIPOQ、FABP4、FASN、SLC2A4、CEBPA），炎症基因增加（TNF 和 IL6）在脂肪细胞分化过程中。值得注意的是，CDO1 基因 KD 导致线粒体呼吸功能降低，同时与线粒体功能相关基因而非生物发生相关基因的表达降低。
目前的研究结果表明 CDO1 在脂肪组织生理学中的重要性，表明其对改善全身代谢谱的贡献。
这项工作得到了西班牙卡洛斯三世健康研究所的研究资助计划 PI16/01173、PI19/01712、PI20/01090 和 PI21/01361、欧洲区域发展基金 (FEDER) 资金以及西班牙糖尿病协会 VII 项基础糖尿病研究项目的支持，这些项目由年轻研究人员领导。
