2. Academic Validation
  3. LncRNA LINK-A Remodels Tissue Inflammatory Microenvironments to Promote Obesity

LncRNA LINK-A Remodels Tissue Inflammatory Microenvironments to Promote Obesity

  • Adv Sci (Weinh). 2023 Dec 25:e2303341. 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
Affiliations

Affiliations

  • 1 MOE Laboratory of Biosystem Homeostasis and Protection, College of Life Sciences, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
  • 2 The Fourth School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310053, China.
  • 3 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.
  • 4 Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), University School of Medicine, International Campus, Zhejiang University, Haining, Zhejiang, 314400, China.
  • 5 The Children's Hospital, National Clinical Research Center for Child Health, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, China.
  • 6 Department of Cell Biology, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310058, China.
  • 7 Department of Biochemistry, Department of Cardiology of Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 313000, China.
  • 8 International School of Medicine, International Institutes of Medicine, The 4th Affiliated Hospital of Zhejiang University School of Medicine, Yiwu, Zhejiang, 322000, China.
  • 9 Department of Cell Biology, Department of General Surgery of Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310016, China.
  • 10 Department of Central Laboratory, The First People's Hospital of Huzhou, Huzhou, Zhejiang, 313000, China.
  • 11 Cancer Center, Zhejiang University, Hangzhou, Zhejiang, 310058, China.
  • 12 Hangzhou Cancer Institution, Affiliated Hangzhou Cancer Hospital, Zhejiang University School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310002, China.
  • 13 College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh, EH16 4SB, UK.
  • 14 Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou, Zhejiang, 310058, China.
  • 15 Future Health Laboratory, Innovation Center of Yangtze River Delta, Zhejiang University, Jiaxing, Zhejiang, 314100, China.
  • 16 Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Hangzhou, Zhejiang, 310009, China.
PMID: 38145352 DOI: 10.1002/advs.202303341
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.

Keywords

HIF1α; LncRNA; high-fat diet; inflammatory microenvironment; obesity; therapeutic target; thermogenesis.

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