Chen Yu, Chen Hui, Wang Ying, Liu Fangzhou, Fan Xiao, Shi Chengyu, Su Xinwan, Tan Manman, Yang Yebin, Lin Bangxing, Lei Kai, Qu Lei, Yang Jiecheng, Zhu Zhipeng, Yuan Zengzhuang, Xie Shanshan, Sun Qinming, Neculai Dante, Liu Wei, Yan Qingfeng, Wang Xiang, Shao Jianzhong, Liu Jian, Lin Aifu
MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China.
Adv Sci (Weinh). 2024 Mar;11(10):e2303341. doi: 10.1002/advs.202303341. Epub 2023 Dec 25.
High-fat diet (HFD)-induced obesity is a crucial risk factor for metabolic syndrome, mainly due to adipose tissue dysfunctions associated with it. However, the underlying mechanism remains unclear. This study has used genetic screening to identify an obesity-associated human lncRNA LINK-A as a critical molecule bridging the metabolic microenvironment and energy expenditure in vivo by establishing the HFD-induced obesity knock-in (KI) mouse model. Mechanistically, HFD LINK-A KI mice induce the infiltration of inflammatory factors, including IL-1β and CXCL16, through the LINK-A/HB-EGF/HIF1α feedback loop axis in a self-amplified manner, thereby promoting the adipose tissue microenvironment remodeling and adaptive thermogenesis disorder, ultimately leading to obesity and insulin resistance. Notably, LINK-A expression is positively correlated with inflammatory factor expression in individuals who are overweight. Of note, targeting LINK-A via nucleic acid drug antisense oligonucleotides (ASO) attenuate HFD-induced obesity and metabolic syndrome, pointing out LINK-A as a valuable and effective therapeutic target for treating HFD-induced obesity. Briefly, the results reveale the roles of lncRNAs (such as LINK-A) in remodeling tissue inflammatory microenvironments to promote HFD-induced obesity.
高脂饮食（HFD）诱导的肥胖是代谢综合征的一个关键风险因素，主要是由于与之相关的脂肪组织功能障碍。然而，其潜在机制仍不清楚。本研究通过建立HFD诱导的肥胖基因敲入（KI）小鼠模型，利用基因筛选确定了一种与肥胖相关的人类长链非编码RNA LINK-A，它是体内连接代谢微环境和能量消耗的关键分子。从机制上讲，HFD LINK-A KI小鼠通过LINK-A/HB-EGF/HIF1α反馈环轴以自我放大的方式诱导包括IL-1β和CXCL16在内的炎症因子浸润，从而促进脂肪组织微环境重塑和适应性产热障碍，最终导致肥胖和胰岛素抵抗。值得注意的是，在超重个体中，LINK-A表达与炎症因子表达呈正相关。值得注意的是，通过核酸药物反义寡核苷酸（ASO）靶向LINK-A可减轻HFD诱导的肥胖和代谢综合征，指出LINK-A是治疗HFD诱导肥胖的一个有价值且有效的治疗靶点。简而言之，这些结果揭示了长链非编码RNA（如LINK-A）在重塑组织炎症微环境以促进HFD诱导肥胖中的作用。
