University of Coimbra, Coimbra Institute for Clinical and Biomedical Research (iCBR), Faculty of Medicine, Coimbra, Portugal; University of Coimbra, Center for Innovative Biomedicine and Biotechnology (CIBB), Coimbra, Portugal; Clinical Academic Center of Coimbra (CACC), Coimbra, Portugal.
Department of Surgery, Universitary Hospital Center of Coimbra, Portugal.
Metabolism. 2024 Apr;153:155788. doi: 10.1016/j.metabol.2024.155788. Epub 2024 Jan 14.
Adipose tissue dysfunction is more related to insulin resistance than body mass index itself and an alteration in adipose tissue function is thought to underlie the shift from metabolically healthy to unhealthy obesity. Herein, we performed a clustering analysis that revealed distinct visceral adipose tissue gene expression patterns in patients with obesity at distinct stages of metabolic dysregulation. We have built a cross-sectional cohort that aims at reflecting the evolution of the metabolic sequelae of obesity with the main objective to map the sequential events that play a role in adipose tissue dysfunction from the metabolically healthy (insulin-sensitive) state to several incremental degrees of metabolic dysregulation, encompassing insulin resistance establishment, pre-diabetes, and type 2 diabetes. We found that insulin resistance is mainly marked by the downregulation of adipose tissue vasculature remodeling-associated gene expression, suggesting that processes like angiogenesis and adaptative expansion/retraction ability suffer early dysregulation. Prediabetes was characterized by compensatory growth factor-dependent signaling and increased response to hypoxia, while type 2 diabetes was associated with loss of cellular response to insulin and hypoxia and concomitant upregulation of inflammatory markers. Our findings suggest a putative sequence of dysregulation of biological processes that is not linear and has multiple distinct phases across the metabolic dysregulation process, ultimately culminating in the climax of adipose tissue dysfunction in type 2 diabetes. Several studies have addressed the transcriptomic changes in adipose tissue of patients with obesity. However, to the best of our knowledge, this is the first study unraveling the potential molecular mechanisms associated with the multi-step evolution of adipose tissue dysfunction along the metabolic sequelae of obesity.
脂肪组织功能障碍与胰岛素抵抗的关系比体重指数本身更为密切，脂肪组织功能的改变被认为是从代谢健康到不健康肥胖的转变的基础。在此，我们进行了聚类分析，揭示了代谢失调不同阶段肥胖患者的内脏脂肪组织基因表达模式的明显差异。我们建立了一个横断面队列，旨在反映肥胖代谢后果的演变，主要目的是绘制从代谢健康（胰岛素敏感）状态到几个递增程度的代谢失调的脂肪组织功能障碍的顺序事件，包括胰岛素抵抗的建立、前驱糖尿病和 2 型糖尿病。我们发现，胰岛素抵抗主要表现为脂肪组织血管重塑相关基因表达的下调，这表明血管生成和适应性扩张/回缩能力等过程很早就受到了失调的影响。前驱糖尿病的特征是生长因子依赖性信号补偿和对缺氧的反应增加，而 2 型糖尿病与细胞对胰岛素和缺氧的反应丧失以及炎症标志物的同时上调有关。我们的研究结果表明，生物过程的失调可能不是线性的，在代谢失调过程中有多个不同的阶段，最终导致 2 型糖尿病脂肪组织功能障碍的高潮。已经有几项研究探讨了肥胖患者脂肪组织的转录组变化。然而，据我们所知，这是第一项阐明与肥胖代谢后果的脂肪组织功能障碍多步演变相关的潜在分子机制的研究。
