Bispo Andressa França Sousa, de Jesus Simao Jussara, Moraes Miguel Ambrizzi, Abel Ana Beatriz Marques, Plata Victor Tadeu Gonçalves, Telles Monica Marques, Santana André Valente, Volpe Paula, Armelin-Correa Lucia Maria, Alonso-Vale Maria Isabel Cardoso
Postgraduate Program in Chemical Biology, Institute of Environmental Sciences, Chemical and Pharmaceutical, Federal University of São Paulo, Diadema, Brazil.
Department of Biological Sciences, Institute of Environmental Sciences, Chemical and Pharmaceutical, Federal University of São Paulo, Diadema, Brazil.
Obesity (Silver Spring). 2025 Aug;33(8):1529-1542. doi: 10.1002/oby.24321. Epub 2025 Jun 16.
This study investigates the correlations between obesity-related plasma markers and epigenetic/inflammatory changes in white adipose tissue (WAT), focusing on adipose-derived stem cells (ASCs). We hypothesize that obesity modulates histone H3K27 marks, modified by demethylases (lysine-specific demethylase 6A and 6B [KDM6A/KDM6B]) and acetylases (CREB-binding protein [CREBBP]/histone acetyltransferase EP300), affecting ASC function.
Serum and visceral WAT (omental region) was collected from male patients (n = 16, 30-50 years old) undergoing elective gastric or bariatric surgery. BMI and obesity markers were correlated with changes in ASCs (transcript expression, proliferation, and secretion) using reverse transcriptase-polymerase chain reaction.
ASCs from individuals with higher BMI exhibited slower proliferation, increased inflammatory profile, and reduced adipogenic potential, with lower expression of key adipogenic genes. H3K27 acetylase transcripts were also negatively correlated with adipogenesis regulators. Moreover, C-C motif chemokine 2 (CCL2) and KDM6A expression was higher in the group with obesity, as were CREBBP and EP300. Finally, leptin levels positively correlated with serum, WAT, and ASC CCL2 expression. In vitro, leptin exposure enhanced CCL2 expression/secretion and increased KDM6A/KDM6B and EP300 transcription.
In vitro leptin exposure enhanced CCL2 expression/secretion and increased KDM6A/KDM6B and EP300 transcription, highlighting how obesity-driven epigenetic mechanisms, including leptin-mediated pathways, disrupt ASC plasticity and perpetuate adipose tissue dysfunction, offering novel therapeutic targets for metabolic disease intervention.
本研究调查肥胖相关血浆标志物与白色脂肪组织（WAT）中表观遗传/炎症变化之间的相关性，重点关注脂肪来源干细胞（ASC）。我们假设肥胖会调节由去甲基化酶（赖氨酸特异性去甲基化酶6A和6B [KDM6A/KDM6B]）和乙酰化酶（CREB结合蛋白[CREBBP]/组蛋白乙酰转移酶EP300）修饰的组蛋白H3K27标记，从而影响ASC功能。
从接受择期胃手术或减肥手术的男性患者（n = 16，年龄30 - 50岁）中收集血清和内脏WAT（网膜区域）。使用逆转录聚合酶链反应将体重指数（BMI）和肥胖标志物与ASC的变化（转录表达、增殖和分泌）进行关联。
BMI较高个体的ASC增殖较慢、炎症特征增加且脂肪生成潜力降低，关键脂肪生成基因的表达较低。H3K27乙酰化酶转录物也与脂肪生成调节因子呈负相关。此外，肥胖组中C - C基序趋化因子2（CCL2）和KDM6A的表达较高，CREBBP和EP300的表达也较高。最后，瘦素水平与血清、WAT和ASC中CCL2的表达呈正相关。在体外，瘦素暴露增强了CCL2的表达/分泌，并增加了KDM6A/KDM6B和EP300的转录。
体外瘦素暴露增强了CCL2的表达/分泌，并增加了KDM6A/KDM6B和EP300的转录，突出了肥胖驱动的表观遗传机制，包括瘦素介导的途径，如何破坏ASC可塑性并使脂肪组织功能障碍持续存在，为代谢疾病干预提供了新的治疗靶点。
