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Bariatric surgery reduces obesity associated breast cancer and enhances response to immunotherapy [Mammary Fat Pad RNA-seq]

ABSTRACT: Patients undergoing bariatric surgery are protected from subsequent breast cancer risk. It is unknown whether weight loss alone or surgery-specific alterations mediate risk reduction. We examined breast cancer in a pre-clinical model of diet induced obesity (DIO) followed by vertical sleeve gastrectomy (VSG) or dietary weight loss. DIO exacerbated tumor progression compared to lean controls, while VSG-induced weight loss reversed this exacerbation. However, dietary interventions were more effective than VSG despite similar reductions in weight and adiposity, potentially due to elevated immunosuppression after VSG. In tumor bearing mice, anti-PD-L1 immunotherapy after VSG improved anti-tumor immunity and potently impaired tumor progression. Thus, weight loss before tumor onset was protective regardless of intervention. Importantly, immunotherapy specifically improved outcomes in VSG.

ORGANISM(S): Mus musculus

PROVIDER: GSE174760 | GEO | 2021/05/21

REPOSITORIES: GEO

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Bariatric surgery reduces obesity associated breast cancer and enhances response to immunotherapy [Tumor - breast cancer RNA-seq]

Project description:Patients undergoing bariatric surgery are protected from subsequent breast cancer risk. It is unknown whether weight loss alone or surgery-specific alterations mediate risk reduction. We examined breast cancer in a pre-clinical model of diet induced obesity (DIO) followed by vertical sleeve gastrectomy (VSG) or dietary weight loss. DIO exacerbated tumor progression compared to lean controls, while VSG-induced weight loss reversed this exacerbation. However, dietary interventions were more effective than VSG despite similar reductions in weight and adiposity, potentially due to elevated immunosuppression after VSG. In tumor bearing mice, anti-PD-L1 immunotherapy after VSG improved anti-tumor immunity and potently impaired tumor progression. Thus, weight loss before tumor onset was protective regardless of intervention. Importantly, immunotherapy specifically improved outcomes in VSG.

2021-05-21 | GSE174761 | 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

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

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

Impact of bariatric surgery on placental transcriptome

Project description:In the present study, we sought to understand the impact of bariatric surgery [using vertical sleeve gastrectomy (VSG)] on transcriptome changes in the placenta . Female Adult, Long Evans were fed high fat diet (HFD, #D03082706, Research Diets) for 4 weeks, divided into sham-VSG or VSG groups, and following surgeries one group of sham-VSG and VSG were switched to normal diet (lean), while one sham-VSG group (obese) continued HFD. At gestdational day 18, placenta tissues harvested from pregnant female rats were processed for Affymetrix microarray and transcriptomic analysis performed.

2018-03-01 | GSE106883 | 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

Single-cell chromatin accessibility and lipid profiling reveals SCD1-dependent metabolic shift in adipocytes induced by bariatric surgery

Project description:We applied single-cell ATAC sequencing and lipid profiling to inguinal and epididymal adipose depots from mice that received sham surgery or vertical sleeve gastrectomy (VSG). We observed depot-specific cellular composition and chromatin accessibility patterns that were altered by VSG. Specifically, accessibility at Scd1, a fatty acid desaturase, was substantially reduced after VSG in mature adipocytes of inguinal but not epididymal depots. This was accompanied by reduced accumulation of SCD1-produced unsaturated fatty acids. Given these findings and reports that reductions in Scd1 attenuate obesity and insulin resistance our results suggest VSG exerts its beneficial effects through an inguinal depot-specific reduction of SCD1 activity.

2021-12-20 | GSE191064 | GEO

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

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

2023-01-27 | GSE218904 | 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

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