Paulí Sara, Oliveras-Cañellas Núria, Moreno-Navarrete José Maria, Castells-Nobau Anna, Ortega Francisco José, Rodriguez-Hermosa Jose Ignacio, Castro Ernesto, Zhang Birong, Zhou You, Gómez-Ambrosi Javier, Crujeiras Ana Belén, Rangel-Zuñiga Oriol Alberto, Garrido-Sanchez Lourdes, Becerril Sara, Pardo María, Romero-Cabrera Juan Luis, Gutierrez-Repiso Carolina, Carreira Marcos C, Macias-Gonzalez Manuel, Martinez-Olmos Miguel Ángel, Frühbeck Gema, Seoane Luisa Maria, López-Miranda José, Tinahones Francisco José, Diéguez Carlos, Mayneris-Perxachs Jordi, Fernández-Real José Manuel
Department of Diabetes, Endocrinology and Nutrition, Dr. Josep Trueta University Hospital, Girona, Spain.
Nutrition, Eumetabolism and Health Group, Girona Biomedical Research Institute (IDIBGI-CERCA), Girona, Spain.
Eur J Clin Invest. 2025 Aug;55(8):e70033. doi: 10.1111/eci.70033. Epub 2025 Mar 26.
Despite growing evidence, the mechanisms connecting adipose tissue (AT) function to type 2 diabetes (T2DM) remain incompletely understood. A detailed analysis of AT transcriptomes could offer valuable insights into this relationship. Here, we examined gene expression patterns in bulk subcutaneous AT, focusing on biological pathways and cellular composition associated with glycated haemoglobin (HbA1c) levels.
A transcriptomic dataset was obtained from subcutaneous AT samples of 901 adults collected during elective surgical procedures. We characterized cellular composition within subcutaneous AT in association with blood HbA1c levels by performing bulk adipose transcriptomes cell deconvolution analysis. We also conducted differential gene expression and overrepresentation analyses. We validated our cross-sectional study using two independent validation cohorts, performing further downstream analyses.
Subcutaneous AT from subjects with increased HbA1c had lower adipocytes, smooth muscle, pericytes and other endothelial cell numbers. Pathways associated with HbA1c levels included cellular senescence and telomere-related pathways and extracellular matrix organisation. We identified the expression of RHO GTPases associated with HbA1c not previously linked to glucose homeostasis, with a possible sexual dimorphism shaped by the obesity state. The findings were confirmed in both longitudinal cohorts. At the gene level, HLA-DR, CCL13, and S100A4 mRNA levels were strongly correlated with HbA1c levels.
This study underscores the utility of AT transcriptome analysis in unravelling T2DM complexities. Our findings enhance knowledge of glucose homeostasis' molecular and cellular underpinnings, paving the way for potential therapeutic targets to mitigate the impact of AT dysfunction in metabolic diseases.
尽管证据越来越多，但脂肪组织（AT）功能与2型糖尿病（T2DM）之间的联系机制仍未完全明了。对AT转录组进行详细分析可能会为这种关系提供有价值的见解。在此，我们研究了皮下大块脂肪组织中的基因表达模式，重点关注与糖化血红蛋白（HbA1c）水平相关的生物学途径和细胞组成。
从901名成年人择期手术期间采集的皮下脂肪组织样本中获得转录组数据集。我们通过进行大块脂肪转录组细胞反卷积分析，将皮下脂肪组织中的细胞组成与血液HbA1c水平相关联。我们还进行了差异基因表达和过度表达分析。我们使用两个独立的验证队列对我们的横断面研究进行了验证，并进行了进一步的下游分析。
HbA1c升高的受试者的皮下脂肪组织中脂肪细胞、平滑肌、周细胞和其他内皮细胞数量较少。与HbA1c水平相关的途径包括细胞衰老和端粒相关途径以及细胞外基质组织。我们确定了与HbA1c相关的RHO GTPases的表达，此前该表达与葡萄糖稳态无关，可能存在由肥胖状态形成的性别差异。这些发现在两个纵向队列中均得到证实。在基因水平上，HLA-DR、CCL13和S100A4 mRNA水平与HbA1c水平密切相关。
本研究强调了脂肪组织转录组分析在揭示T2DM复杂性方面的实用性。我们的发现增强了对葡萄糖稳态分子和细胞基础的认识，为减轻脂肪组织功能障碍对代谢疾病影响的潜在治疗靶点铺平了道路。
