This manuscript identifies a human obesity‐associated long noncoding RNA, LINK‐A, by generating a de novo knock‐in(KI) mouse model to demonstrate it as a critical molecule bridging the metabolic microenvironment and energy expenditure in vivo via establishing a high‐fat diet (HFD)‐induced obesity KI mouse model and uncovering the mechanisms regulated by the LINK‐A/HB‐EGF/HIF1α feedback loop. This evidence concerns the gene HIF1A and obesity due to melanocortin 4 receptor deficiency.