LncRNA LINK-A Remodels Tissue Inflammatory Microenvironments to Promote Obesity,Advanced Science

当前位置： X-MOL 学术 › Adv. Sci. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

LncRNA LINK-A Remodels Tissue Inflammatory Microenvironments to Promote Obesity
Advanced Science ( IF 14.3 ) Pub Date : 2023-12-25 , DOI: 10.1002/advs.202303341
Yu Chen ₁ , Hui Chen ₁ , Ying Wang ₁ , Fangzhou Liu ₁ , Xiao Fan ₁ , Chengyu Shi ₁ , Xinwan Su ₁ , Manman Tan ₁ , Yebin Yang ₂ , Bangxing Lin ₃ , Kai Lei ₁ , Lei Qu ₁ , Jiecheng Yang ₁ , Zhipeng Zhu ₁ , Zengzhuang Yuan ₄ , Shanshan Xie _{5,

6} , Qinming Sun _{7,

8} , Dante Neculai _{8,

9} , Wei Liu _{7,

8} , Qingfeng Yan ₁ , Xiang Wang _{3,

10} , Jianzhong Shao ₁ , Jian Liu _{4,

11,

12,

13} , Aifu Lin _{1,

8,

11,

14,

15,

16}

Affiliation

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.
Key Laboratory of Integrated Oncology and Intelligent Medicine of Zhejiang Province, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310006, China.
Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), University School of Medicine, International Campus, Zhejiang University, Haining, Zhejiang, 314400, China.
The Children's Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China.
Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
Department of Biochemistry, Department of Cardiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 313000, China.
International School of Medicine, International Institutes of Medicine, The 4th Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China.
Department of Cell Biology, Department of General Surgery of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, China.
Department of Central Laboratory, The First People's Hospital of Huzhou, Huzhou, Zhejiang, 313000, China.
Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
Hangzhou Cancer Institution, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310002, China.
College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh, EH16 4SB, UK.
Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou, Zhejiang, 310058, China.
Future Health Laboratory, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, Zhejiang, 314100, China.
Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Hangzhou, Zhejiang, 310009, China.

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.

中文翻译：

LncRNA LINK-A 重塑组织炎症微环境以促进肥胖

高脂饮食（HFD）引起的肥胖是代谢综合征的一个重要危险因素，主要是由于与之相关的脂肪组织功能障碍。然而，其根本机制仍不清楚。本研究通过建立 HFD 诱导的肥胖敲入 (KI) 小鼠模型，利用基因筛选来鉴定与肥胖相关的人类 lncRNA LINK-A作为桥接体内代谢微环境和能量消耗的关键分子。机制上，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在内的炎症因子的浸润，从而促进脂肪组织微环境重塑和适应性生热障碍，最终导致肥胖和胰岛素抵抗。值得注意的是，超重个体中LINK-A 的表达与炎症因子的表达呈正相关。值得注意的是，通过核酸药物反义寡核苷酸（ASO）靶向LINK-A可以减轻HFD引起的肥胖和代谢综合征，表明LINK-A是治疗HFD引起的肥胖的有价值且有效的治疗靶点。简而言之，结果揭示了 lncRNA（例如LINK-A ）在重塑组织炎症微环境以促进 HFD 诱导的肥胖中的作用。

更新日期：2023-12-25

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南