biostudies-literatureAbdollahi MNIDDK NIH HHSNCI NIH HHS102792https://www.ebi.ac.uk/biostudies/studies/S-EPMC12794071biostudies-literatureUnknown37(1)The long noncoding RNA (lncRNA) lnc-megacluster (lncMGC) is implicated in diabetic kidney disease and pancreatic islet dysfunction. However, its role in obesity and insulin resistance (IR) is unknown. Herein, we investigated the regulatory role of lncMGC in obesity and adipose dysfunction using lncMGC knockout-(KO) mice and further determined the translational potential of lncMGC-based therapeutics for obesity using GapmeR antisense oligonucleotides in wild-type and partially humanized-lncMGC mice. We found lncMGC is upregulated in perigonadal white adipose (gWAT) and brown adipose tissues (BAT) from high-fat diet (HFD)-induced obese mice along with increased endoplasmic reticulum stress signaling. Inhibition of lncMGC in mice via genetic ablation or GapmeRs targeting mouse or human lncMGCMolecular therapy. Nucleic acidsMetabolic beneficial effects of targeting a long non-coding RNA, lnc-megacluster, in obesity.PMC12794071R01 DK143577R01 DK065073P30 CA033572R01 DK081705Abdollahi MNandi JYang LPillai RKZhang LLanting LMalek VRezaei AKato MKebrom LHuang WTanwar VSMa KNatarajan RfalseMetabolic beneficial effects of targeting a long non-coding RNA, lnc-megacluster, in obesity.The long noncoding RNA (lncRNA) lnc-megacluster (lncMGC) is implicated in diabetic kidney disease and pancreatic islet dysfunction. However, its role in obesity and insulin resistance (IR) is unknown. Herein, we investigated the regulatory role of lncMGC in obesity and adipose dysfunction using lncMGC knockout-(KO) mice and further determined the translational potential of lncMGC-based therapeutics for obesity using GapmeR antisense oligonucleotides in wild-type and partially humanized-lncMGC mice. We found lncMGC is upregulated in perigonadal white adipose (gWAT) and brown adipose tissues (BAT) from high-fat diet (HFD)-induced obese mice along with increased endoplasmic reticulum stress signaling. Inhibition of lncMGC in mice via genetic ablation or GapmeRs targeting mouse or human lncMGC2026-01-01T00:00:00Z2026 Mar2026-06-06T19:36:54.192Z2026-06-04T03:12:24.748ZS-EPMC127940714153201410.1016/j.omtn.2025.102792