Metabolic 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 lncMGC displayed protective effects against HFD-induced IR, weight gain, and associated adipose dysfunction, with some sex-specific differences. In parallel, key lncMGC targets regulating gWAT and BAT functions were altered. In gWAT, loss of lncMGC either in KO mice or through GapmeR treatment improved angiogenesis and reduced adipocyte hypertrophy and inflammation. In BAT, lncMGC deficiency or inhibition enhanced mitochondrial thermogenesis and mitophagy markers. Collectively, these new findings underscore the pathogenic role of lncMGC in adipose dysfunction and the therapeutic potential of targeting key lncRNAs for obesity and associated metabolic dysfunction.