Zhu Qiuyan, Jia Xiaoli, Li Shupeng, Feng Jinxing
State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology & Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, 518055, People's Republic of China.
Department of Psychiatry, University of Toronto, Toronto, ON, Canada.
Cell Commun Signal. 2025 Jul 26;23(1):356. doi: 10.1186/s12964-025-02359-w.
Intake of nutrients and water from diet to maintain life, a typical physiological function of gut, is highly dependent on the extensive immune network, whose imbalance is easy to induce inflammatory bowel disease (IBD) including Crohn's disease (CD) and ulcerative colitis (UC). Clinical strategies to completely cure IBD are poor, so it is urgent to develop novel drugs or targets. Adiponectin (APN), an adipokine from adipocytes, regulates energy metabolism and immune response. High levels APN are inversely associated with CD severity UC colonic fibrosis. However, the mechanism by which APN interferes with IBD remains unclear. This review aims to analyze correlation and molecular mechanism between APN and IBD. APN and AdipoR2 proteins are highly expressed in colon which is a primary organ of IBD, and the target intersection of APN and IBD is huge. APN may interfere with lipid metabolism in IBD individuals through AdipoR1/2, but regulates neural and peripheral immune by AdipoR1 but not AdipoR2 and mediates nutritional and energy homeostasis through AdipoR2 rather than AdipoR1. Besides, APN mediates CRP and IL-6 through AdipoR1/2, AMPK and TNF-α through AdipoR1 and PI3K-Akt, PPARA and PPARG through AdipoR2 to affect IBD progression, which depends on direct interaction between APPL1 and AdipoR1/2. Unexpectedly, AMPK and TNF-α may also interact directly with AdipoR1. APN regulates CD through AdipoR1/2-metabolism process and UC through AdipoR1-inflammation axis or AdipoR2-fibrosis process. APN analogues or AdipoRon which is a dual agonist of AdipoR1/2 potentially reduces colonic fibrosis in UC and fistulae in CD, promotes mucosal healing, repairs intestinal microbiota homeostasis and increases autophagy to alleviate IBD symptoms by weakening TNF-α, IL-6, NLRP3, TGFB1 activities and aggrandizing P-AKT, PPARA, PPARG, INS, IRS1/2, IGF-1, TIMP1, NOD2, SIRT1 levels.
从饮食中摄取营养物质和水分以维持生命是肠道的一项典型生理功能，这高度依赖于广泛的免疫网络，该网络失衡易引发包括克罗恩病（CD）和溃疡性结肠炎（UC）在内的炎症性肠病（IBD）。目前完全治愈IBD的临床策略效果不佳，因此开发新型药物或靶点迫在眉睫。脂联素（APN）是一种来自脂肪细胞的脂肪因子，可调节能量代谢和免疫反应。高水平的APN与CD严重程度、UC结肠纤维化呈负相关。然而，APN干扰IBD的机制尚不清楚。本综述旨在分析APN与IBD之间的相关性及分子机制。APN和AdipoR2蛋白在作为IBD主要器官的结肠中高表达，且APN与IBD的靶点交集巨大。APN可能通过AdipoR1/2干扰IBD个体的脂质代谢，但通过AdipoR1而非AdipoR2调节神经和外周免疫，并通过AdipoR2而非AdipoR1介导营养和能量稳态。此外，APN通过AdipoR1/2介导CRP和IL - 6，通过AdipoR1介导AMPK和TNF - α，通过AdipoR2介导PI3K - Akt、PPARA和PPARG，从而影响IBD进展，这依赖于APPL1与AdipoR1/2之间的直接相互作用。出乎意料的是，AMPK和TNF - α也可能与AdipoR1直接相互作用。APN通过AdipoR1/2 - 代谢过程调节CD，通过AdipoR1 - 炎症轴或AdipoR2 - 纤维化过程调节UC。APN类似物或作为AdipoR1/2双重激动剂的AdipoRon可能会减轻UC中的结肠纤维化和CD中的瘘管，促进黏膜愈合，修复肠道微生物群稳态，并通过减弱TNF - α、IL - 6、NLRP3、TGFB1活性以及增强P - AKT、PPARA、PPARG、INS、IRS1/2、IGF - 1、TIMP1、NOD2、SIRT1水平来增加自噬，从而缓解IBD症状。
