1636-P: Targeting a Long Noncoding RNA lncMGC Ameliorates Obesity-Associated Adipose Tissue Dysfunction in Mice

The long noncoding RNA (lncRNA) lncMGC, plays a pathological role in the diabetic kidney. However, its role in obesity, insulin resistance (IR), and type 2 diabetes is not known. Here we examined whether targeting lncMGC with a locked nucleic acid-modified LNA-GapmeR antisense oligonucleotide ameliorates weight gain, adipose dysfunction, and IR in high-fat diet (HFD) fed mice. Mechanistically, we also examined whether lncMGC promotes adipose tissue dysfunction via up/down-regulation of targets/genes involved in perigonadal white adipose tissue (gWAT) and brown adipose tissue (BAT) function and mitochondrial health. We tested lncMGC-GapmeR in HFD-fed wild-type (WT) and partially humanized lncMGC (hlncMGC) mice to assess the translational potential of targeting human lncMGC for obesity/IR. Male and female C57BL/6 WT and female hlncMGC mice were fed chow diet (Con) or HFD and injected with GapmeR-negative control (HFD-NC), or GapmeR targeting lncMGC (HFD-Gap) at 5 mg/kg/week/8 weeks. Body composition was assessed with Echo-MRI, and plasma insulin levels by ELISA. Using qPCR, we measured angiogenesis and adipogenesis markers in gWAT and mitochondrial function-related genes in BAT. Sections from gWAT and BAT were stained for histopathology. We found WT HFD-Gap and hlncMGC HFD-Gap mice exhibited significantly lower body weight, total body fat, and insulin levels compared to HFD-NC. HFD-induced adipocyte hypertrophy, gWAT inflammation markers (Tnfα, F4/80), impaired angiogenesis (Cd31, Vegfb), and adipogenesis (Pparg, cebpb) related-genes were attenuated in HFD-Gap mice versus HFD-NC. Furthermore, lncMGC GapmeR significantly reversed HFD-induced BAT whitening and impaired mitochondrial markers (Fis1, Ppargc1α, Tfam, Dio2) versus HFD-NC. These results show GapmeR targeting lncMGC alleviates HFD-induced obesity and adipose dysfunction via changes in key gWAT and BAT markers, highlighting its therapeutic potential for obesity and its complications.