Montreal Diabetes Research Center - Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Canada.
Montreal Diabetes Research Center - Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Canada.
Mol Metab. 2023 Dec;78:101822. doi: 10.1016/j.molmet.2023.101822. Epub 2023 Oct 12.
Pro-inflammatory polarization of adipose tissue macrophages (ATMs) plays a critical role in the pathogenesis of obesity-associated chronic inflammation. However, little is known about the role of lipids in the regulation of ATMs polarity and inflammation in response to metabolic stress. Deletion of α/β-hydrolase domain-containing 6 (ABHD6), a monoacylglycerol (MAG) hydrolase, has been shown to protect against diet-induced obesity and insulin resistance.
Here we investigated the immunometabolic role of macrophage ABHD6 in response to nutrient excess using whole-body ABHD6-KO mice and human and murine macrophage cell-lines treated with KT203, a selective and potent pharmacological ABHD6 inhibitor.
KO mice on high-fat diet showed lower susceptibility to systemic diet-induced inflammation. Moreover, in the setting of overnutrition, stromal vascular cells from gonadal fat of KO vs. control mice contained lower number of M1 macrophages and exhibited enhanced levels of metabolically activated macrophages (MMe) and M2 markers, oxygen consumption, and interleukin-6 (IL-6) release. Likewise, under in vitro nutri-stress condition, inhibition of ABHD6 in MMe-polarized macrophages attenuated the expression and release of pro-inflammatory cytokines and M1 markers and induced the upregulation of lipid metabolism genes. ABHD6-inhibited MMe macrophages showed elevated levels of peroxisome proliferator-activated receptors (PPARs) and 2-MAG species. Notably, among different MAG species, only 2-MAG treatment led to increased levels of PPAR target genes in MMe macrophages.
Collectively, our findings identify ABHD6 as a key component of pro-inflammatory macrophage activation in response to excess nutrition and implicate an endogenous macrophage lipolysis/ABHD6/2-MAG/PPARs cascade, as a lipid signaling and immunometabolic pathway, which favors the anti-inflammatory polarization of ATMs in obesity.
脂肪组织巨噬细胞（ATMs）的促炎极化在肥胖相关慢性炎症的发病机制中起着关键作用。然而，人们对脂质在调节 ATMs 极性和代谢应激反应中的炎症作用知之甚少。脂肪酶 ABHD6 的缺失已被证明可以防止饮食诱导的肥胖和胰岛素抵抗。
在这里，我们使用全身 ABHD6-KO 小鼠和经 KT203（一种选择性和有效的药理学 ABHD6 抑制剂）处理的人源和鼠源巨噬细胞系，研究了巨噬细胞 ABHD6 在应对营养过剩时的免疫代谢作用。
高脂肪饮食喂养的 KO 小鼠对全身饮食诱导的炎症的敏感性较低。此外，在营养过剩的情况下，KO 小鼠与对照组相比，其生殖腺脂肪的基质血管细胞中 M1 巨噬细胞数量较少，表现出代谢激活的巨噬细胞（MMe）和 M2 标志物、耗氧量和白细胞介素-6（IL-6）释放增加。同样，在体外营养应激条件下，MMe 极化的巨噬细胞中 ABHD6 的抑制作用减弱了促炎细胞因子和 M1 标志物的表达和释放，并诱导脂质代谢基因的上调。ABHD6 抑制的 MMe 巨噬细胞显示出过氧化物酶体增殖物激活受体（PPARs）和 2-MAG 水平的升高。值得注意的是，在不同的 MAG 物种中，只有 2-MAG 处理导致 MMe 巨噬细胞中 PPAR 靶基因的水平增加。
总之，我们的研究结果表明 ABHD6 是对营养过剩时促炎巨噬细胞激活的关键组成部分，并提示内源性巨噬细胞脂肪分解/ABHD6/2-MAG/PPARs 级联反应作为一种脂质信号和免疫代谢途径，有利于肥胖时 ATMs 的抗炎极化。
