LncRNA LINK‐A Remodels Tissue Inflammatory Microenvironments to Promote Obesity

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.

Long Noncoding RNAs in Diet-Induced Metabolic Diseases

“…Mechanistically, LINKA facilitates the heparin-binding (HB)-EGF-mediated recruitment of two kinases, breast tumor kinase (BRK) and leucin-rich repeat kinase 2 (LRRK2), to the EGFR-GPNMB (epidermal growth factor receptor–glycoprotein NMB) dimer, which results in the phosphorylation of HIF1α at two sites, leading to HIF1α stabilization and activation under normoxic conditions [ 38 ]. Recently, LINKA has also been shown to be a human-specific lncRNA that is induced in the breast tissue, subcutaneous WAT, and visceral adipose tissue of overweight patients and whose expression correlates with increasing body mass indices [ 39 ]. In a mouse model, in which human LINKA had been knocked-in into the mouse genome, LINKA overexpression promoted high-fat-diet (HFD)-induced obesity and insulin resistance [ 39 ].…”

“…Recently, LINKA has also been shown to be a human-specific lncRNA that is induced in the breast tissue, subcutaneous WAT, and visceral adipose tissue of overweight patients and whose expression correlates with increasing body mass indices [ 39 ]. In a mouse model, in which human LINKA had been knocked-in into the mouse genome, LINKA overexpression promoted high-fat-diet (HFD)-induced obesity and insulin resistance [ 39 ]. Moreover, mice with LINKA overexpression suffer from inflammatory alterations in adipose tissue as well as mammary glands.…”

“…LINKA promotes the production of pro-inflammatory factors in mouse mammary glands via stabilization of the transcription factor HIF1α, which, in turn, transcriptionally activates inflammatory genes, such as interleukin 1 beta ( Il1b ) and C-X-C motif chemokine ligand 16 ( Cxcl16 ). This is associated with suppressed energy expenditure and a reduced adaptive thermogenic function in mice, as demonstrated by a significant reduction in uncoupling protein 1 ( Ucp1 ), which facilitates heat generation in the mitochondria of BAT and related thermogenesis genes in several adipose tissues after cold exposure [ 39 ]. On a molecular level, LINKA cooperates with HB-EGF to stabilize HIF1α ( Figure 1 a), potentially via a similar mechanism previously described in human breast cancer cells [ 38 ].…”