Obesity is associated with chronic inflammation and metabolic complications, including insulin resistance (IR). Immune cells drive inflammation through the rewiring of intracellular metabolism. However, the impact of obesity-related IR on the metabolism and functionality of circulating immune cells, like monocytes, remains poorly understood. To increase insight into the inter-individual variation of immunometabolic signatures among individuals and their role in the development of IR, we assessed systemic and tissue-specific IR and circulating immune markers, and we characterized metabolic signatures and cytokine secretion of circulating monocytes from 194 individuals with a BMI≥25kg/m2. Monocyte metabolic signatures were defined using extracellular acidification rates (ECAR) to estimate glycolysis and oxygen consumption rates (OCR) for oxidative metabolism. Although monocyte metabolic signatures and function based on cytokine secretion varied greatly among subjects, they were strongly associated with each other. The ECAR/OCR ratio, representing the balance between glycolysis and oxidative metabolism, was negatively associated with fasting insulin, systemic IR, and liver-specific IR. These results indicate that monocytes from individuals with IR were relatively more dependent on oxidative metabolism, while monocytes from more insulinsensitive individuals were more dependent on glycolysis. Additionally, circulating CXCL11 was negatively associated with the degree of systemic IR and positively with the ECAR/OCR ratio in monocytes, suggesting that individuals with high IR and a monocyte metabolic dependence on oxidative metabolism also have lower levels of circulating CXCL11. Our findings suggest that monocyte metabolism is related to obesity-associated IR progression and deepen insights into the interplay between innate immune cell metabolism and IR development in humans.

中文翻译：

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肥胖和胰岛素抵抗人类循环单核细胞的免疫代谢特征

肥胖与慢性炎症和代谢并发症有关，包括胰岛素抵抗（IR）。免疫细胞通过细胞内代谢的重新连接来驱动炎症。然而，与肥胖相关的IR对单核细胞等循环免疫细胞的代谢和功能的影响仍知之甚少。为了深入了解个体间免疫代谢特征的个体差异及其在 IR 发展中的作用，我们评估了全身和组织特异性 IR 和循环免疫标记物，并表征了 194 名个体的循环单核细胞的代谢特征和细胞因子分泌BMI≥25kg/m2。使用细胞外酸化率（ECAR）来定义单核细胞代谢特征，以估计氧化代谢的糖酵解和耗氧率（OCR）。尽管单核细胞的代谢特征和基于细胞因子分泌的功能在受试者之间差异很大，但它们彼此之间密切相关。 ECAR/OCR 比率代表糖酵解和氧化代谢之间的平衡，与空腹胰岛素、全身 IR 和肝脏特异性 IR 呈负相关。这些结果表明，来自IR个体的单核细胞相对更依赖于氧化代谢，而来自胰岛素敏感个体的单核细胞更依赖于糖酵解。此外，循环CXCL11与全身IR程度呈负相关，与单核细胞中的ECAR/OCR比率呈正相关，这表明具有高IR和单核细胞代谢依赖于氧化代谢的个体也具有较低水平的循环CXCL11。我们的研究结果表明，单核细胞代谢与肥胖相关的 IR 进展有关，并加深了对人类先天免疫细胞代谢与 IR 发展之间相互作用的认识。