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Downregulation of hepatic lncRNA Gm19619 improves gluconeogenesis and lipogenesis following vertical sleeve gastrectomy in mice [ChIRP-Seq]

ABSTRACT: 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 identified a hepatic lncRNA Gm19619, which was 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 promoted hepatic gluconeogenesis with the elevated expression of G6pc and Pck1. In contrast, AAV-CasRx mediated knockdown of Gm19619 in HFD-fed mice significantly improved hepatic glucose and lipid metabolism. Mechanistically, Gm19619 was enriched along genomic regions encoding leptin receptor (Lepr) and the transcriptional factor Foxo1, as revealed in chromatin isolation by RNA purification (ChIRP) assay and was confirmed to modulate their transcription in the mouse liver. In conclusion, Gm19619 may enhance gluconeogenesis and lipid metabolism in the liver.

ORGANISM(S): Mus musculus

PROVIDER: GSE218905 | GEO | 2023/01/27

REPOSITORIES: GEO

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Project description:Bariatric surgeries such as the Vertical Sleeve Gastrectomy (VSG) are invasive but provide the most effective long-term metabolic improvements in individuals with obesity and/or Type 2 diabetes. These powerful effects of manipulating the gastrointestinal tract point to an important role of gastrointestinal signals in regulating both energy balance and metabolism. To that end, we have used mouse models of VSG to identify key gut signals that mediate these beneficial effects. Previous data from our rodent model of VSG led us to hypothesize a potential role for the hormone Fibroblast-Growth Factor15/19 (mouse/human ortholog) which pharmacologically can regulate many aspects of energy homeostasis and glucose handling. FGF15 is expressed in ileal enterocytes of the small intestine and is released postprandially. Like many other gut hormones, postprandial plasma concentrations of the human ortholog FGF19 and ileal FGF15 expression in mice increase after VSG. We generated intestinal-specific FGF15 knock out (VilCreERT2; Fgf15f/f) mice and controls, which were maintained on 60% high-fat diet. VSG resulted in increased plasma bile acid levels. However, intestinal-specific FGF15 knock out mice had considerably higher levels of circulating total and hydrophobic bile acids after VSG. Unlike what we had predicted, intestinal-specific FGF15 knock out mice lost more weight after VSG as a result of increased lean tissue loss compared to control mice. Further, the loss of bone mineral density and bone marrow adipose tissue observed after VSG in control mice was even greater in intestinal-specific FGF15 knock out mice, perhaps secondary to anemia and elevated erythropoietin/FGF23. Finally the effect of VSG to improve glucose tolerance and to reduce hepatic cholesterol was also absent in intestinal-specific FGF15 knock out mice. These data point to an important role for intestinal FGF15 to protect the organism from deleterious effects of bile acid toxicity after VSG.

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Downregulation of hepatic lncRNA Gm19619 improves gluconeogenesis and lipogenesis following vertical sleeve gastrectomy in mice [ChIRP-Seq]

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