Ying Lingwen, Zhang Mingliang, Ma Xiaojing, Si Yiming, Li Xiaoya, Su Jiaorong, Yin Jun, Bao Yuqian
Department of Endocrinology and Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai Clinical Center for Diabetes, Shanghai Key Clinical Center for Metabolic Disease, Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai, China.
Department of Endocrinology and Metabolism, Shanghai Eighth People's Hospital, Shanghai, China.
Front Cell Dev Biol. 2021 May 20;9:672032. doi: 10.3389/fcell.2021.672032. eCollection 2021.
Here, we studied the metabolic function of LAMTOR1 from macrophages using LAMTOR1 macrophage-specific knockout (MKO) mice. LAMTOR1 MKO mice showed resistance to high-fat diet (HFD)-induced obesity, lipid steatosis, and glucose metabolic disorders, with elevated levels of pro-inflammatory cytokines. The energy expenditure, oxygen consumption, and CO production increased significantly in HFD-fed MKO vs. wild-type (WT) mice. HE and immunohistochemistry staining showed a remarkable CD68 Kupffer cell accumulation in the liver. Additionally, flow cytometry revealed that the proportion of macrophages and monocytes increased significantly in the liver of MKO mice. Of note, these macrophages were probably derived from the bone marrow since the proportion of CD11b cells as well as the proliferative activity was also increased in the context of femoral bone marrow cells. In addition, the Kupffer cells of both WT and KO mice were double-positive for the M1 (CD86) and M2 (CD206) markers. However, the expression of both M1 and M2 macrophage-related genes was increased in the liver of HFD-fed KO mice. Murine primary hepatocytes and Kupffer cells were further isolated and incubated with oleic acid for 24 h. The glucose output of primary hepatocytes from MKO mice was not affected. However, decreased lipid tolerance was observed in LAMTOR1-deficient Kupffer cells. Overall, our results suggest that LAMTOR1 deficiency in macrophages prevents obesity and metabolic disorders via the accumulation of Kupffer cells in the liver and the consequent hyper-inflammation and increased energy expenditure. Therefore, our results provide a new perspective for macrophage-derived LAMTOR1 in the context of systemic metabolism.
在此，我们使用LAMTOR1巨噬细胞特异性敲除（MKO）小鼠研究了巨噬细胞中LAMTOR1的代谢功能。LAMTOR1 MKO小鼠对高脂饮食（HFD）诱导的肥胖、脂质脂肪变性和葡萄糖代谢紊乱具有抗性，促炎细胞因子水平升高。与野生型（WT）小鼠相比，高脂饮食喂养的MKO小鼠的能量消耗、氧气消耗和二氧化碳产生显著增加。苏木精-伊红（HE）染色和免疫组织化学染色显示肝脏中CD68库普弗细胞显著积聚。此外，流式细胞术显示MKO小鼠肝脏中巨噬细胞和单核细胞的比例显著增加。值得注意的是，这些巨噬细胞可能来源于骨髓，因为股骨骨髓细胞中CD11b细胞的比例以及增殖活性也增加了。此外，WT和KO小鼠的库普弗细胞对M1（CD86）和M2（CD206）标志物均呈双阳性。然而，高脂饮食喂养的KO小鼠肝脏中M1和M2巨噬细胞相关基因的表达均增加。进一步分离小鼠原代肝细胞和库普弗细胞，并用油酸孵育24小时。MKO小鼠原代肝细胞的葡萄糖输出不受影响。然而，在LAMTOR1缺陷的库普弗细胞中观察到脂质耐受性降低。总体而言，我们的结果表明，巨噬细胞中LAMTOR1的缺乏通过肝脏中库普弗细胞的积累以及随之而来的炎症加剧和能量消耗增加来预防肥胖和代谢紊乱。因此，我们的结果为全身代谢背景下巨噬细胞来源的LAMTOR1提供了一个新的视角。
