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. In parallel, key lncMGC targets involved in gWAT and BAT functions were altered. The metabolic beneficial effects in gWAT were accompanied by improved angiogenesis, reduced adipocyte hypertrophy, and inflammation. Notably, lowering lncMGC levels in HFD-fed lncMGC KO or via GapmeR treatment enhanced BAT functional markers, mitochondrial thermogenic program/structure, 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. Overall design: Eight-week-old male and female C57BL/6J WT, lncMGC KO and partially humanized lncMGC female mice were randomly divided into groups and fed a control chow or HFD [(60% kcal from fat) for 10 or 20 weeks. Body weight and blood glucose levels were measured during the experiments. At the end of the studies, mice were fasted overnight, then, after euthanasia, plasma was collected to measure insulin levels. Perigonadal white adipose tissue (gWAT), interscapular brown adipose tissue (BAT) and pancreas were harvested for molecular and histological analysis.