OBJECTIVE: Macrophage accumulation in metabolically active tissues during obesity is common in both animals and humans, but the lipid signaling mechanisms that trigger macrophage inflammation remain unclear. This study investigates the role of Ces1d, an unconventional lipase, in regulating macrophage inflammation under nutritional stress. METHODS: A myeloid-specific Ces1d knockout (LysM-Cre-Ces1d (floxed/floxed), KO) mouse model was used for the studies. For in vitro tests, bone marrow-derived macrophages (BMDMs) from control (Ces1d (floxed/floxed), WT) and KO mice were assessed for migration, polarization, and activation. For in vivo experiments, WT and KO mice were induced to obesity via a high-fat diet (HFD) and subjected to metabolic characterization. Adipose tissue, liver, and serum samples were analyzed histologically and biochemically. Endogenous macrophages and T cells from adipose tissue were isolated and analyzed for functional interactions by flow cytometry. RESULTS: Ces1d expression changes during the differentiation of monocytes into macrophages in both mice and humans. Loss of Ces1d causes larger lipid droplets, with increased accumulation of triacylglycerol (TAG) and diacylglycerol (DAG), and impaired lipid signaling in KO macrophages. Lipid dysregulation in macrophages triggers pro-inflammatory activation, enhancing migration, activation, and polarization toward an M1-like phenotype. The pro-inflammatory macrophages further promote CD3+CD8+ T cell accumulation in obese adipose tissue, which contributes to worsened metabolic disorders, including more severe fatty liver, increased local inflammation in adipose tissue, and impaired systemic glucose tolerance in KO mice on a high-fat diet. CONCLUSIONS: This study demonstrates Ces1d is a crucial factor in maintaining lipid homeostasis in macrophages. Loss of Ces1d leads to metabolic dysregulation in macrophages and other immune cells during obesity.
Functional regulation of macrophages by Ces1d-mediated lipid signaling in immunometabolism.
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作者:Shao Long J, Elizondo Fathima, Gao Feng, Habib Rabie, Li Xin, Pham Katherine, Ysaguirre Jazmin, Elizondo Maryam, Shirazi Shirindokht, Eckel-Mahan Kristin L, Hartig Sean, Wu Huaizhu, Sun Kai
期刊: | Molecular Metabolism | 影响因子: | 6.600 |
时间: | 2025 | 起止号: | 2025 Jul;97:102166 |
doi: | 10.1016/j.molmet.2025.102166 |
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