de Jesus Simão Jussara, de Sousa Bispo Andressa França, Plata Victor Tadeu Gonçalves, Abel Ana Beatriz Marques, Telles Monica Marques, Armelin-Correa Lucia Maria, Alonso-Vale Maria Isabel Cardoso
Post-graduate Program in Chemical Biology - Institute of Environmental Sciences, Chemical and Pharmaceutical, Federal University of São Paulo - UNIFESP, Diadema, Brazil.
Post-graduate Program in Nutrition -Paulista School of Medicine, Federal University of São Paulo - UNIFESP, Sao Paulo, Brazil.
Metabol Open. 2024 Nov 30;24:100336. doi: 10.1016/j.metop.2024.100336. eCollection 2024 Dec.
In obesity, C-C chemokine ligand 2 (CCL2) plays a critical role in recruiting macrophages to white adipose tissue (WAT), contributing to chronic inflammation. In this study, we sought to explore the effects of fish oil (FO) on CCL2 expression and histone (H3K27)-modifying enzymes in both human model of preadipocytes and primary adipose-derived stem cells (ASCs). Present findings in preadipocytes lineage evidenced that lipopolysaccharide (LPS) increased (∼5.8-fold) and (∼3.8-fold) expression, modulating H3K27 modifying enzymes expression, including KDM6B and EP300. FO, in turn, significantly attenuated LPS-induced expression and secretion and downregulated and , elucidating an important mechanism of action involved in the anti-inflammatory role of FO. We next isolated mature hypertrophied adipocytes from patient with overweight and exposed to LPS, resulting in increased (∼3.8-fold) and (∼4.5-fold) expression, effects significantly attenuated by FO. We also generated adipocyte-conditioned medium (ACM) and exposed ASCs to LPS or ACM for up to 72 h to assess CCL2/MCP-1 secretion. ACM from hypertrophied adipocytes stimulated increased expression, which was partially reduced by FO. LPS treatment of primary ASCs led to a marked increase in CCL2 secretion, which was completely abolished by FO after 6 h, highlighting its potent anti-inflammatory effect. After 72 h, FO consistently maintained lower levels of CCL2, even during sustained inflammatory stimulation, underscoring its ability to modulate chronic inflammation. Additionally, the inhibition of NF-κB with JSH-23 mimicked the effects of FO on expression, further suggesting that the anti-inflammatory actions of FO may involve NF-κB signaling. In conclusion, FO attenuates CCL2 expression and secretion in both preadipocytes and ASCs, providing evidence of its potential in modulating inflammation in WAT progenitor cells by modulating histone-modifying enzymes and inflammatory pathways.
在肥胖状态下，C-C趋化因子配体2（CCL2）在招募巨噬细胞至白色脂肪组织（WAT）中发挥关键作用，进而导致慢性炎症。在本研究中，我们试图探讨鱼油（FO）对人前脂肪细胞模型和原代脂肪来源干细胞（ASC）中CCL2表达及组蛋白（H3K27）修饰酶的影响。人前脂肪细胞系的现有研究结果表明，脂多糖（LPS）使CCL2表达增加（约5.8倍）以及MCP-1表达增加（约3.8倍），同时调节H3K27修饰酶的表达，包括KDM6B和EP300。反过来，FO显著减弱LPS诱导的CCL2表达和分泌，并下调KDM6B和EP300，阐明了FO抗炎作用的重要作用机制。接下来，我们从超重患者中分离出成熟肥大的脂肪细胞并使其暴露于LPS中，导致CCL2表达增加（约3.8倍）以及MCP-1表达增加（约4.5倍），FO可显著减弱这些作用。我们还制备了脂肪细胞条件培养基（ACM），并使ASC暴露于LPS或ACM中长达72小时，以评估CCL2/MCP-1的分泌。肥大脂肪细胞的ACM刺激可使CCL2表达增加，而FO可使其部分降低。LPS处理原代ASC导致CCL2分泌显著增加，6小时后FO可完全消除这种增加，突出了其强大的抗炎作用。72小时后，即使在持续的炎症刺激下，FO仍能持续维持较低水平的CCL2，强调了其调节慢性炎症的能力。此外，用JSH-23抑制NF-κB可模拟FO对CCL2表达的影响，进一步表明FO的抗炎作用可能涉及NF-κB信号通路。总之，FO可减弱前脂肪细胞和ASC中CCL2的表达和分泌，为其通过调节组蛋白修饰酶和炎症途径调节WAT祖细胞炎症的潜力提供了证据。
