Wang Yongheng, Lin Ritian, Wang Fangtao, Fu Huijun, Wang Xia, Jin Fengshan, Wang Qiao, Shu Weigang
Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China; Department of Gastroenterology, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, Shanghai, 200072, China.
Department of Gastroenterology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, 200120, China.
Mol Metab. 2025 Jul 5;99:102203. doi: 10.1016/j.molmet.2025.102203.
Hypertrophied mesenteric adipose tissue (MAT) wrapped around the inflamed intestine, also known as creeping fat (CrF), is a classic pathological characteristic of Crohn's disease (CD). Recent studies revealed that the abnormal mesentery in CD exhibits a white-to-beige transformation (known as white adipose browning), which may be a compensatory mechanism for disease attenuation. However, its underlying causes and mechanisms remain unknown.
The beige MAT samples from patients with CD and normal white MAT samples from patients without CD were collected, and targeted metabolome analysis was performed. Interleukin-10 gene knockout (IL-10) and 2,4,6-trinitrobenzenesulphonic acid solution (TNBS)-induced colitis mice were used to evaluate the effects of kynurenic acid (KYNA) on mesenteritis and colitis. Mesenteric explants and adipocytes were collected and cultured to assess the effects of KYNA on adipose tissue browning and macrophage inflammation.
Targeted metabolomic sequencing revealed that KYNA exhibited the highest level of upregulation in the beige MAT of CD, which was tightly correlated with the browning marker UCP-1, inflammatory factors, and adipokines. In vivo experiments demonstrated that KYNA triggered the white-to-beige transformation of MAT in IL-10 and TNBS-induced colitis mice, which further alleviated mesenteritis and colitis. Additionally, mesenteric explants and adipocytes displayed a browning phenotype with KYNA co-incubation, and their supernatants significantly induced M2 macrophage polarization and inhibited inflammation. Mechanistically, KYNA induced MAT browning and regulated disease procession of CD via GPR35-ERK1/2-PGC-1α signaling pathway.
This study provides novel insights into the browning transformation of the mesentery in CD and suggests a potential approach for clinical therapy.
包裹在发炎肠道周围的肥大肠系膜脂肪组织（MAT），也称为爬行脂肪（CrF），是克罗恩病（CD）的经典病理特征。最近的研究表明，CD中异常的肠系膜呈现白色到米色的转变（称为白色脂肪褐变），这可能是疾病减轻的一种代偿机制。然而，其潜在原因和机制仍不清楚。
收集CD患者的米色MAT样本和非CD患者的正常白色MAT样本，并进行靶向代谢组分析。使用白细胞介素-10基因敲除（IL-10）和2,4,6-三硝基苯磺酸溶液（TNBS）诱导的结肠炎小鼠来评估犬尿喹啉酸（KYNA）对肠系膜炎症和结肠炎的影响。收集并培养肠系膜外植体和脂肪细胞，以评估KYNA对脂肪组织褐变和巨噬细胞炎症的影响。
靶向代谢组测序显示，KYNA在CD的米色MAT中上调水平最高，这与褐变标记物解偶联蛋白-1、炎症因子和脂肪因子密切相关。体内实验表明，KYNA在IL-10和TNBS诱导的结肠炎小鼠中引发了MAT的白色到米色转变，这进一步减轻了肠系膜炎症和结肠炎。此外，肠系膜外植体和脂肪细胞与KYNA共孵育时呈现褐变表型，其上清液显著诱导M2巨噬细胞极化并抑制炎症。机制上，KYNA通过GPR35-ERK1/2-PGC-1α信号通路诱导MAT褐变并调节CD的疾病进程。
本研究为CD中肠系膜的褐变转化提供了新的见解，并提出了一种潜在的临床治疗方法。
