The mechanisms governing adipose tissue macrophage (ATM) metabolic adaptation during diet-induced obesity (DIO) are poorly understood. In obese adipose tissue, ATMs are exposed to lipid fluxes, which can influence the activation of specific inflammatory and metabolic programs and contribute to the development of obesity-associated insulin resistance and other metabolic disorders. In the present study, we demonstrate that the membrane ATP-binding cassette g1 (Abcg1) transporter controls the ATM functional response to fatty acids (FAs) carried by triglyceride-rich lipoproteins, which are abundant in high-energy diets. Mice genetically lacking Abcg1 in the myeloid lineage presented an ameliorated inflammatory status in adipose tissue and reduced insulin resistance. Abcg1-deficient ATMs exhibited a less inflammatory phenotype accompanied by a low bioenergetic profile and modified FA metabolism. A closer look at the ATM lipidome revealed a shift in the handling of FA pools, including a redirection of saturated FAs from membrane phospholipids to lipid droplets, leading to a reduction in membrane rigidity and neutralization of proinflammatory FAs. ATMs from human individuals with obesity presented the same reciprocal relationship between ABCG1 expression and this inflammatory and metabolic status. Abolition of this protective, anti-inflammatory phenotype in Abcg1-deficient ATMs was achieved through restoration of lipoprotein lipase (Lpl) activity, thus delineating the importance of the Abcg1/Lpl axis in controlling ATM metabolic inflammation. Overall, our study identifies the rewiring of FA pools by Abcg1 as a major pathway orchestrating ATM plasticity and insulin resistance in DIO.

中文翻译：

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ABCG1 通过重新连接饱和脂肪酸池来协调肥胖症患者脂肪组织巨噬细胞的可塑性和胰岛素抵抗


饮食诱导的肥胖 （DIO） 期间控制脂肪组织巨噬细胞 （ATM） 代谢适应的机制知之甚少。在肥胖的脂肪组织中，ATM 暴露于脂质通量中，这会影响特定炎症和代谢程序的激活，并导致肥胖相关胰岛素抵抗和其他代谢紊乱的发展。在本研究中，我们证明膜 ATP 结合盒 g1 （Abcg1） 转运蛋白控制对富含甘油三酯的脂蛋白携带的脂肪酸 （FA） 的 ATM 功能反应，这些脂蛋白在高能量饮食中含量丰富。骨髓谱系中遗传缺乏 Abcg1 的小鼠在脂肪组织中的炎症状态得到改善，胰岛素抵抗降低。Abcg1 缺陷型 ATM 表现出较少的炎症表型，伴有低生物能量谱和 FA 代谢修饰。仔细观察 ATM 脂质组揭示了 FA 池处理方式的转变，包括饱和 FA 从膜磷脂重定向到脂滴，导致膜刚性降低和促炎 FA 的中和。来自肥胖人类个体的 ATM 在 ABCG1 表达与这种炎症和代谢状态之间呈现相同的互惠关系。通过恢复脂蛋白脂肪酶 （Lpl） 活性，消除了 Abcg1 缺陷型 ATM 中的这种保护性抗炎表型，从而描绘了 Abcg1/Lpl 轴在控制 ATM 代谢炎症中的重要性。总体而言，我们的研究确定 Abcg1 对 FA 池的重新布线是协调 DIO 中 ATM 可塑性和胰岛素抵抗的主要途径。