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Downregulation of hepatic lncRNA Gm19619 improves gluconeogenesis and lipogenesis following vertical sleeve gastrectomy in mice [RNA-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: GSE218904 | GEO | 2023/01/27

REPOSITORIES: GEO

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

Project description: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.

2023-01-27 | GSE218905 | GEO

Vertical sleeve gastrectomy reverses diet-induced gene-regulatory changes impacting lipid metabolism

Project description:Vertical sleeve gastrectomy (VSG) produces sustainable weight loss, remission of type 2 diabetes (T2D), and improvement of nonalcoholic fatty liver disease (NAFLD). However, the molecular mechanisms underlying the metabolic benefits of VSG have remained elusive. We have previously demonstrated that diet-induced obesity leads to chromatin modifications in the liver of mice. We demonstrate here that VSG in C57BL/6J wild-type male mice can reverse these chromatin modifications and thereby impact the expression of key metabolic genes. Genes involved in lipid metabolism, especially omega-6 fatty acid metabolism, are up-regulated in livers of mice after VSG while genes in inflammatory pathways are down-regulated after VSG. Consistent with gene expression changes, regulatory regions near genes involved in inflammatory response displayed decreased chromatin accessibility after VSG. Our results indicate that VSG induces global regulatory changes that impact hepatic inflammatory and lipid metabolic pathways, providing new insight into the mechanisms underlying the beneficial metabolic effects induced by VSG.

2017-07-13 | GSE94842 | GEO

Hepatic transcriptomic changes following equivalent weight loss by calorie restriction or vertical sleeve gastrectomy in mice with hepatic steatosis

Project description:Sleeve gastrectomy (VSG) leads to improvement in hepatic steatosis, associated with weight loss. The aims of this study were to investigate whether VSG leads to weight-loss independent improvements in liver steatosis in mice with diet-induced obesity (DIO); and to transcriptomically profile hepatic changes in mice undergoing VSG. Methods: Mice with DIO were treated with VSG, sham surgery with subsequent food restriction to weight-match to the VSG group (Sham-WM), or sham surgery with return to unrestricted diet (Sham-Ad lib). Hepatic transcriptomics were investigated at the end of the study period and treatment groups were compared with mice undergoing sham surgery only (Sham-Ad lib). Results: VSG led to much greater improvement in liver steatosis than Sham-WM (liver triglyceride mg/mg 2.5 ± 0.1, 2.1 ± 0.2, 1.6 ± 0.1 for Sham-AL, Sham-WM and VSG respectively; p=0.003). Homeostatic model assessment of insulin resistance was improved following VSG only (51.2 ± 8.8, 36.3 ± 5.3, 22.3 ± 6.1 for Sham-AL, Sham-WM and VSG respectively; p=0.03). The glucagon-alanine index, a measure of glucagon resistance, fell with VSG but was significantly increased in Sham-WM (9.8 ± 1.7, 25.8 ± 4.6 and 5.2 ± 1.2 in Sham Ad-lib, Sham-WM and VSG respectively; p=0.0003). Genes downstream of glucagon receptor signalling which govern fatty acid synthesis (Acaca, Acacb, Me1, Acyl, Fasn and Elovl6) were downregulated following VSG but upregulated in Sham-WM. Conclusion: Changes in glucagon sensitivity may contribute to weight-loss independent improvements in hepatic steatosis following VSG.

2024-03-13 | GSE225843 | GEO

Intestinal epithelial adaptations to vertical sleeve gastrectomy defined at single-cell resolution

Project description:The gut plays a key role in regulating metabolic health. Dietary factors disrupt intestinal physiology and contribute to obesity and diabetes, whereas bariatric procedures such as vertical sleeve gastrectomy (VSG) cause gut adaptations that induce robust metabolic improvements. However, our understanding of these adaptations at the cellular and molecular levels remains limited. In a validated murine model, we leverage single-cell transcriptomics to determine how VSG impacts different cell lineages of the small intestinal epithelium. We define cell type-specific genes and pathways that VSG rescues from high-fat diet perturbation and characterize additional rescue-independent changes brought about by VSG. We show that Paneth cells have increased expression of the gut peptide Reg3g after VSG. We also find that VSG restores pathways pertaining to mitochondrial respiration and cellular metabolism, especially within crypt-based cells. Overall, our study provides unprecedented molecular resolution of VSG’s therapeutic effects on the gut epithelium.

2024-03-27 | GSE234189 | GEO

RNAseq Analysis of Mouse Stomach and Intestines Following Vertical Sleeve Gastrectomy

Project description:Bariatric surgery, an effective treatment for obesity and diabetes, leads to profound remodeling of whole body energy homeostasis. We utilized a mouse model of vertical sleeve gastrectomy (VSG), a common bariatric surgery as a tool to identify novel secreted proteins and peptides that might act as important metabolic regulators. We analyzed gene expression in the stomach and intestines following VSG or sham surgery in diet-induced obese mice and sought to identify differentially regulated genes encoding secreted proteins/peptides.

2017-10-14 | GSE104956 | GEO

mRNA Sequencing Analysis of Subcutanous White Adipose Tissue Transcriptomes from Vertical Sleeve Gastrectomy and Sham-operated WT-Mice

Project description:Purpose: VSG has leads to a restructuring of WAT anantomy and physiology. The study aimed to understand how the (rhythmic) transcriptome is affected by these changes, especially in regard to metabolism and circadian clock genes. Methods: Animals were fed HFD for approx. 10 weeks to be considered overweight (ca. 35g body weight). 32 animals underwent either sham or VSG surgery. After 3-4 days of postoperative care with liquid diet and analgetic treatment, subcutanous WAT biopsies from Zeitgeber time 1, 7, 13, and 19 were collected 9 days after surgery. mRNA sequencing was conducted with Illumina HiSeq 2000 and rhythm analysis of filtered genes performed with JTK_CYCLE. Results: We found a reduction of cycling genes after VSG (sham: 2,493 vs. VSG: 1,013) in parallel to a reduced amplitude of cycling genes shared between VSG and sham animals (paired t-test p < 0.05) independent of the expression of core clock genes. Genes associated with lipid metabolic pathways (fatty acid breakdown and lipogenesis) showed altered circadian regulation. Conclusions: We found VSG to reorganize WAT rhythmic transcriptome in a specific manner independent of the core clock machinery.

2021-06-21 | GSE162671 | GEO

Vertical sleeve gastrectomy triggers fast β-cell recovery upon overt diabetes

Project description:This dataset consists of single-cell RNA-seq (10X) data of pancreatic islets isolated from healthy and diabetic db/db mice that underwent VSG surgery, Sham surgery (Control) and Sham surgery + pair-feeding (Calorie-restriction control).

2021-09-01 | GSE174194 | GEO

Gene expression profiling of the ileum following vertical sleeve gastrectomy compared to pair-fed sham surgery controls in mice with high-fat diet-induced obesity.

Project description:We report the expression profiles of ileal samples extracted from obese male C57Bl6 mice following vertical sleeve gastrectomy or sham surgery, focusing of gene signatures indicative of altered bile acid metabolism. We induced obesity in male C57bl6 mice through a high-fat diet. At 8 weeks, they were submitted to either a vertical sleeve gastrectomy (VSG) or a sham surgery; following surgery VSG mice were fed ad libitum while sham controls were pair-fed (SPF) to the experimental animals. During the four perioperative days, mice were fed a liquid Osmolite diet. Approximately 8 weeks after surgery mice were fasted overnight and gavaged with .5mL Osmolite; after one hour mice were sacrificed and the terminal ileum were extracted. RNA was extracted, quantified, and compared between VSG and SPF experimental groups.

2014-03-27 | E-GEOD-53782 | biostudies-arrayexpress

TST knockout liver proteome iTRAQ and persulfidome

Project description:Impaired hepatic glucose and lipid metabolism are hallmarks of type–2 diabetes. Increased sulfide production or sulfide–donor compounds may beneficially regulate hepatic metabolism. Disposal of sulfide through the sulfide oxidation pathway (SOP) is critical for maintaining sulfide within a safe physiological range. We show that mice lacking the liver–enriched mitochondrial SOP enzyme thiosulfate sulfur–transferase (Tst—/— mice) exhibit high circulating sulfide, increased gluconeogenesis, hypertriglyceridemia and fatty liver. Unexpectedly, hepatic sulfide levels are normal in Tst—/— mice due to exaggerated induction of sulfide disposal, with an associated suppression of global protein persulfidation and nuclear respiratory factor–2 target protein levels. Hepatic proteomic and persulfidomic profiles converge on gluconeogenesis and lipid metabolism, revealing a selective deficit in medium–chain fatty acid oxidation in Tst—/— mice. We reveal a critical role for TST in hepatic metabolism that has implications for sulfide-donor strategies in the context of metabolic disease.

2021-11-11 | PXD028909 | Pride

Liver Med23 ablation improves glucose and lipid metabolism and prevent diet-induced obesity

Project description:Mediator complex function as an integrative hub for transcriptional regulation. Here we show that Mediator subunit MED23 regulate glucose and lipid metabolism via FOXO1 in liver. Here, we have generated a liver-specific Med23-knockout (LMKO) mouse and found that Med23-deletion in liver improved glucose and lipid metabolism, as well as insulin responsiveness, and prevented diet-induced obesity. Mechanistically, MED23 participated in gluconeogenesis and cholesterol synthesis by interacting with FOXO1. Disruption of this interaction by hepatic Med23-deletion impaired the Mediator and RNAP II recruitment and partially reduced the expression of the FOXO1 target genes. Remarkably, acute hepatic Med23 knockdown in db/db mice significantly improved insulin sensitivity. Overall, our data revealed Mediator MED23 as a critical regulator of glucose and lipid metabolism, suggesting novel therapeutic strategies against metabolic diseases.

2015-03-16 | GSE48966 | GEO

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