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Long non-coding RNAs (lncRNAs) are emerging important epigenetic regulators in metabolic processes. Whether they contribute to the metabolic effects of vertical sleeve gastrectomy (VSG), one of the most effective treatments for sustainable weight loss and metabolic improvement, is unknown. Herein, we identify a hepatic lncRNA Gm19619, which is strongly repressed by VSG but highly up-regulated by diet-induced obesity and overnight-fasting in mice. Forced transcription of Gm19619 in the mouse liver significantly promotes hepatic gluconeogenesis with the elevated expression of G6pc and Pck1. In contrast, AAV-CasRx mediated knockdown of Gm19619 in high-fat diet-fed mice significantly improves hepatic glucose and lipid metabolism. Mechanistically, Gm19619 is enriched along genomic regions encoding leptin receptor (Lepr) and transcription factor Foxo1, as revealed in chromatin isolation by RNA …