Downregulation of hepatic lncRNA Gm19619 improves gluconeogenesis and lipogenesis following vertical sleeve gastrectomy in mice

Vertical sleeve gastrectomy (VSG) is a highly effective bariatric surgery for sustainable weight loss and metabolic improvement. While several molecular mechanisms contributing to VSG's effects have been identified, including the role of TGR5 and reduced intestinal bile acids, much remains unknown. Long non-coding RNAs (lncRNAs) are emerging as significant regulators of metabolic processes. This study investigates the potential role of lncRNAs in mediating the metabolic effects of VSG, focusing on a specific hepatic lncRNA, Gm19619, whose expression is responsive to VSG and metabolic conditions.

Previous research has highlighted the importance of lncRNAs in metabolic regulation. For example, LeXis, induced by liver X receptors (LXR), affects cholesterol biosynthesis, while CHROME promotes cholesterol efflux. Incob, crucial for leptin expression, is repressed in diet-induced obesity. However, the involvement of lncRNAs in the metabolic effects of bariatric surgery remained largely unexplored before this study.

This study utilized established VSG mouse models to screen for lncRNAs whose hepatic expression was altered by VSG. Gm19619, strongly downregulated by VSG and upregulated by diet-induced obesity and fasting, was identified. Its function was characterized using adeno-associated viruses (AAV) for forced expression and AAV-CasRx for knockdown in mice. Chromatin isolation by RNA purification (ChIRP) assay was performed to identify Gm19619's genomic targets. Metabolic parameters were assessed via glucose tolerance tests (GTT), insulin tolerance tests (ITT), pyruvate tolerance tests (PTT), and analysis of serum and hepatic lipid levels. Gene expression was analyzed via qPCR and western blotting.

VSG strongly suppressed Gm19619 transcription. Gm19619 was significantly induced by both diet-induced obesity and overnight fasting. Forced Gm19619 expression via AAV significantly enhanced hepatic gluconeogenesis, as evidenced by increased G6pc and Pck1 expression and impaired glucose metabolism (GTT and ITT). Conversely, AAV-CasRx-mediated knockdown of Gm19619 in high-fat diet (HFD)-fed mice significantly improved both hepatic glucose and lipid metabolism, reducing fasting blood glucose, improving glucose tolerance (GTT), insulin sensitivity (ITT), and repressing gluconeogenesis (PTT). Hepatic triglyceride levels were also significantly reduced, accompanied by decreased expression of lipogenic genes and increased expression of lipolysis and fatty acid beta-oxidation genes. ChIRP analysis revealed Gm19619 binding to Lepr and Foxo1 genomic regions. Gm19619 overexpression downregulated Lepr expression and upregulated Foxo1, while Gm19619 knockdown had the opposite effect. This suggests Gm19619 promotes gluconeogenesis by activating the Foxo1 pathway and facilitates lipogenesis by inhibiting Lepr signaling.

This study demonstrates that Gm19619, a hepatic lncRNA upregulated in obesity and fasting, is significantly downregulated by VSG. Its manipulation directly impacts hepatic glucose and lipid metabolism, suggesting a key role in mediating VSG's metabolic benefits. Gm19619's modulation of Lepr and Foxo1 provides a mechanistic explanation for its effects on both gluconeogenesis and lipogenesis. While the reduction in circulating leptin after VSG has been observed, this study highlights the liver-specific role of Gm19619 in mediating metabolic changes. The findings offer potential therapeutic targets for obesity and related metabolic disorders, potentially avoiding the need for invasive surgery.

This research reveals a novel mechanism by which VSG improves metabolic outcomes, involving the downregulation of hepatic lncRNA Gm19619. Gm19619's modulation of Lepr and Foxo1 signaling pathways underscores its influence on both glucose and lipid metabolism. Future research could focus on developing targeted therapies that modulate Gm19619 expression or its interactions with key proteins, offering a less invasive alternative to VSG.

The study was conducted in mice, and the results may not be directly translatable to humans. The focus was on hepatic Gm19619, while other lncRNAs and tissues may contribute to VSG's overall metabolic effects. Further investigation is needed to fully elucidate the complex interplay of various factors influencing VSG's benefits.