Faculty, Staff and Student Publications
Publication Date
7-1-2025
Journal
Molecular Metabolism
DOI
10.1016/j.molmet.2025.102166
PMID
40349771
PMCID
PMC12145999
PubMedCentral® Posted Date
5-9-2025
PubMedCentral® Full Text Version
Post-print
Abstract
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.
Keywords
Animals, Macrophages, Mice, Mice, Knockout, Obesity, Signal Transduction, Diet, High-Fat, Humans, Lipid Metabolism, Mice, Inbred C57BL, Male, Inflammation, Lipase, Triglycerides, Adipose Tissue, Ces1d, Macrophages, Inflammation, Lipid signaling, Immunometabolism
Published Open-Access
yes
Recommended Citation
Shao, Long J; Elizondo, Fathima; Gao, Feng; et al., "Functional Regulation of Macrophages by Ces1d-Mediated Lipid Signaling in Immunometabolism" (2025). Faculty, Staff and Student Publications. 2203.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/2203
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