Role of microRNA-147 in adipose tissue macrophages during obesity
Immunology
Cardiology, Angiology
Cell Biology
Final Report Abstract
The global obesity epidemic is a significant risk factor for diet-related severe diseases such as metabolic syndrome, type 2 diabetes, cardiovascular disease, and certain cancers, closely linked to high-calorie Western-style diets. This connection is mediated by metabolic endotoxemia, characterized by low levels of gutderived lipopolysaccharides (LPS) in the bloodstream, which trigger chronic low-grade inflammation. This study explored the potential of neutralizing endotoxins with anti-LPS monoclonal antibodies to combat metabolic disorders in mice with high-fat diet-induced obesity and atherosclerosis. We used a multi-omics approach to understand how metabolic endotoxemia affects target organs locally and systemically. Hyperlipidemic Ldlr–/– mice were fed a high-cholesterol, high-carbohydrate Western-type diet (HCC) for 22 weeks, including eight weeks of antibody treatment. Results showed that LPS neutralization lowered endotoxin levels in plasma, epididymal white adipose tissue (eWAT), liver, and arterial lesions. This treatment improved insulin sensitivity and lipid profiles by reducing oxidized low-density lipoprotein (oxLDL) and balancing VLDL, LDL, and HDL levels. Moreover, LPS neutralization slowed body weight gain and reduced obesity-driven inflammation in eWAT. Atherosclerotic lesions and macrophage accumulation in the aortic root were reduced, suggesting a lowered cardiovascular risk. Multi-omics analysis, including transcriptomics, proteomics, metabolomics, and lipidomics, showed that LPS neutralization affected critical pathways related to inflammation, oxidative stress, and metabolism. Specifically, genes in adipose tissue macrophages (ATMs) showed an anti-inflammatory shift and enhanced mitochondrial function. In plasma, proteomic and metabolomic data showed reductions in oxidative stress- and neuroinflammatory-associated metabolites and increased L-arginine levels. Lipidomics identified a notable decrease in pro-inflammatory lysophosphatidylcholines (LPC), a lipid class contributing to atherosclerosis, and reduced oxLDL. The findings suggest that targeting endotoxemia by anti-LPS monoclonal antibodies improved metabolic and cardiovascular outcomes by reducing inflammation, oxidative stress, and pro-atherogenic lipids, presenting a potential therapeutic strategy for metabolic syndrome and atherosclerosis. In WP2, we studied the role of miR-147 in macrophages in diet-induced metabolic disorders, following our previous findings that miR-147 is selectively upregulated in M1 polarized macrophages and ATMs of HCC-fed obese mice. We applied a 24-week HCC feeding study using dual-fluorescent reporter macrophagespecific Mir147 deficiency mice. Male mice lacking Mir147 showed increased body and adipose tissue weights, more significant ATM infiltration, and more crown-like structures in eWAT, particularly in LDL receptor-deficient models, suggesting a protective role of macrophage miR-147 against obesity and adipose inflammation. Ongoing transcriptomic analyses aim to identify miR-147 targets in ATMs during obesity, while 4D live-cell imaging is being used to assess the effects of miR-147 on ATM behaviors.
