Reverse causality has made it difficult to establish the causal directions between obesity and prediabetes and obesity and insulin resistance. To disentangle whether obesity causally drives prediabetes and insulin resistance already in non-diabetic individuals, we utilized the UK Biobank and METSIM cohort to perform a Mendelian randomization (MR) analyses in the non-diabetic individuals. Our results suggest that both prediabetes and systemic insulin resistance are caused by obesity (p = 1.2×10⁻³ and p = 3.1×10⁻²⁴). As obesity reflects the amount of body fat, we next studied how adipose tissue affects insulin resistance. We performed both bulk RNA-sequencing and single nucleus RNA sequencing on frozen human subcutaneous adipose biopsies to assess adipose cell-type heterogeneity and mitochondrial (MT) gene expression in insulin resistance. We discovered that the adipose MT gene expression and body fat percent are both independently associated with insulin resistance (p≤0.05 for each) when adjusting for the decomposed adipose cell-type proportions. Next, we showed that these 3 factors, adipose MT gene expression, body fat percent, and adipose cell types, explain a substantial amount (44.39%) of variance in insulin resistance and can be used to predict it (p≤2.64×10⁻⁵ in 3 independent human cohorts). In summary, we demonstrated that obesity is a strong determinant of both prediabetes and insulin resistance, and discovered that individuals’ adipose cell-type composition, adipose MT gene expression, and body fat percent predict their insulin resistance, emphasizing the critical role of adipose tissue in systemic insulin resistance.

反向因果关系使得很难确定肥胖和前驱糖尿病以及肥胖和胰岛素抵抗之间的因果方向。为了弄清楚肥胖是否会导致非糖尿病个体已经发生糖尿病前期和胰岛素抵抗，我们利用 UK Biobank 和 METSIM 队列对非糖尿病个体进行了孟德尔随机化 (MR) 分析。我们的结果表明，前驱糖尿病和全身性胰岛素抵抗都是由肥胖引起的（p = 1.2×10 ^-3和 p = 3.1×10 ^-24). 由于肥胖反映了体内脂肪量，我们接下来研究了脂肪组织如何影响胰岛素抵抗。我们对冷冻人皮下脂肪活组织检查进行了批量 RNA 测序和单核 RNA 测序，以评估胰岛素抵抗中的脂肪细胞类型异质性和线粒体 (MT) 基因表达。我们发现，在调整分解的脂肪细胞类型比例时，脂肪 MT 基因表达和体脂百分比均与胰岛素抵抗独立相关（每个 p≤0.05）。接下来，我们发现这 3 个因素，脂肪 MT 基因表达、体脂百分比和脂肪细胞类型，解释了胰岛素抵抗的大量 (44.39%) 差异，并可用于预测它 (p≤2.64×10 ^{- 5个}在 3 个独立的人类队列中）。总之，我们证明肥胖是前驱糖尿病和胰岛素抵抗的重要决定因素，并发现个体的脂肪细胞类型组成、脂肪 MT 基因表达和体脂百分比可预测他们的胰岛素抵抗，强调脂肪组织的关键作用在全身性胰岛素抵抗中。