A dynamic subcutaneous adipose transcriptome of human insulin resistance identifies a molecular predisposition shared with visceral adipose tissue

Subcutaneous adipose tissue (SAT) is classically viewed as a metabolic buffer for lipid deposition during positive caloric balance, while visceral adipose tissue (VAT) is viewed as the dominant contributor and prime mediator of insulin resistance (IR) and cardiometabolic disease risk. Nevertheless, a growing body of data suggests that similar morphologic and molecular changes may occur in SAT as in VAT during obesity. In addition, while pro-inflammatory immune changes within adipose are thought to drive IR there is increasing data implicating a role for adipocytes and stromal populations especially in humans. Here, we identified a transcriptional landscape of IR in SAT of 220 humans across the spectrum of obesity and IR states, highlighting a broad range of metabolic pathways central to IR. Using single cell and nucleus deconvolution and statistical learning techniques, we identified a 35-gene signature that (1) achieved high predictive accuracy for homeostatic model of IR (HOMA-IR) across BMI; (2) was expressed across a variety of non-immune cell populations (most prominently adipocytes and adipocyte stem and precursor cells [ASPCs]), with primarily “protective” IR associations for adipocyte transcripts and “deleterious” associations for macrophage transcripts; (3) displayed a high concordance between SAT and VAT (greater than non-IR associated genes). Multiple SAT genes exhibited dynamic expression 5-years after weight loss surgery and with insulin stimulation. Finally, using available expression quantitative trait loci in SAT and/or VAT, we demonstrate similar genetic effect sizes of SAT and VAT on type 2 diabetes and BMI, suggesting underlying similarities in genetic determinants of IR between adipose depots. These results implicate a dynamic transcriptional architecture of IR that resides in both immune and non-immune populations in SAT and that is shared with VAT, nuancing the current VAT-centric concept of IR in humans. Overall design: The discovery cohort consisted of 76 samples collected from individuals with obesity and pre-diabetes by lipoaspiration from the subcutaneous adipose depot. These individuals had matching metadata including height, weight, and measures of insulin resistance.

皮下脂肪组织（Subcutaneous Adipose Tissue, SAT）传统上被视为热量正平衡时脂质沉积的代谢缓冲库，而内脏脂肪组织（Visceral Adipose Tissue, VAT）则被认为是胰岛素抵抗（Insulin Resistance, IR）及心血管代谢疾病风险的主要驱动因素与核心介导因子。然而，越来越多的研究证据表明，肥胖状态下SAT与VAT可出现相似的形态学与分子学改变。此外，尽管脂肪组织内的促炎免疫改变被认为是IR的致病驱动因素，但越来越多的研究显示，脂肪细胞及基质细胞群在IR的发生发展中发挥关键作用，这一点在人类研究中尤为突出。
本研究对220名覆盖全谱系肥胖与IR状态的受试者的SAT组织进行转录组分析，揭示了与IR密切相关的广泛代谢通路特征。通过单细胞与细胞核解卷积技术及统计学习方法，我们鉴定出一组35基因特征集，该特征集具备以下特点：（1）在不同身体质量指数（Body Mass Index, BMI）分层中，对胰岛素抵抗稳态模型（Homeostatic Model Assessment for Insulin Resistance, HOMA-IR）均具有较高的预测准确率；（2）可在多种非免疫细胞群中表达，其中以脂肪细胞及脂肪干细胞与前体细胞（Adipocyte Stem and Precursor Cells, ASPCs）最为显著；且脂肪细胞转录本与IR主要呈保护性关联，而巨噬细胞转录本则与IR呈有害性关联；（3）SAT与VAT的基因表达谱一致性较高，且该一致性高于非IR相关基因。
多项SAT基因在减重手术后5年及胰岛素刺激条件下呈现动态表达变化。最后，借助SAT和/或VAT中的表达数量性状基因座（expression Quantitative Trait Loci, eQTLs）数据，我们证实SAT与VAT对2型糖尿病及BMI的遗传效应量相似，提示不同脂肪库的IR遗传决定机制存在内在相似性。
上述研究结果表明，IR的动态转录调控架构同时存在于SAT的免疫与非免疫细胞群中，且与VAT共享该特征，修正并细化了当前以VAT为核心的人类IR认知。
研究整体设计：发现队列共纳入76份样本，均来自肥胖伴前驱糖尿病受试者，通过脂肪抽吸术获取其皮下脂肪组织。所有受试者均配有配套的临床元数据，包括身高、体重及胰岛素抵抗相关检测指标。