LncRNA <i>LINK‐</i>A Remodels Tissue Inflammatory Microenvironments to Promote Obesity
Yu Chen, Hui Chen, Ying Wang, Fangzhou Liu, Xiao Fan, Chengyu Shi, Xinwan Su, Manman Tan, Yebin Yang, B. Lin, Kai Lei, Lei Qu, Jiecheng Yang, Zhi-Peng Zhu, Zengzhuang Yuan, Shanshan Xie, Qinming Sun, Dante Neculai, Wei Liu, Qingfeng Yan, Xiang Wang, Jian‐Zhong Shao, Jian Liu, Aifu Lin
Abstract
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.