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Liraglutide + PYY3-36 combination therapy mimics effects of Roux-en-Y bypass on early NAFLD whilst lacking-behind in metabolic improvements.

ABSTRACT: Background: Non-alcoholic fatty liver disease (NAFLD) is common in the general population. Treatment options for NAFLD are very limited, GLP-1 analogues, however, seem to be effective. Roux-en-Y gastric bypass (RYGB) is highly effective in terms of body weight loss and improves histologic and metabolic markers of NAFLD. We directly compared the effects of RYGB and a treatment with liraglutide and/or peptide tyrosine tyrosine 3-36 (PYY3-36) on early NAFLD. Methods: High-fat diet (HFD)-induced obese male Wistar rats were randomized into 6 treatment groups: RYGB, sham-operation (Sham), liraglutide (0.4mg/kg/day), PYY3-36 (0.1mg/kg/day), li-raglutide+PYY3-36 and saline. Following intervention and after an observation period of 4 weeks liver samples were histologically evaluated, ELISAs and RT-qPCRs +RNA sequencing were per-formed. Results: RYGB and liraglutide+PYY3-36 induced a similar body weight loss and marked histological improvements with significantly less steatosis compared to sham/saline. However, only RYGB induced significant metabolic improvements and mRNA expression changes. Con-clusions: liraglutide+PYY3-36 combination therapy mimics the positive effects of RYGB on weight reduction and on hepatic steatosis, while its effects on insulin resistance and adipose tissue dys-function (adiponectin/leptin ratio) lack behind RYGB.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE192425 | GEO | 2022/02/16

REPOSITORIES: GEO

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Roux-en-Y gastric bypass and caloric restriction but not gut hormone-based treatments profoundly impact the hypothalamic transcriptome in obese rats

Project description:Background: The hypothalamus is an important brain region for the regulation of energy balance. Roux-en-Y gastric bypass (RYGB) surgery and gut hormone-based treatments are known to reduce body weight, but their effects on hypothalamic gene expression and signaling pathways are poorly studied. Methods: Diet-induced obese male Wistar rats were randomized into the following groups: RYGB, sham-operation, sham + body weight-matched (BWM) to the RYGB group, osmotic minipump delivering PYY3-36 (0.1mg/kg/day), liraglutide s.c. (0.4mg/kg/day), PYY3-36+liraglutide and saline. All groups (except BWM) were kept on a free choice of high- and low-fat diets. Four weeks after interventions, hypothalami were collected for RNA-sequencing. Results: While rats in the RYGB, BWM and PYY3-36+liraglutide groups had comparable reductions in body weight, only RYGB and BWM treatment had a major impact on hypothalamic gene expression. In these groups, hypothalamic leptin receptor expression as well as the JAK–STAT, PI3K-Akt and AMPK signaling pathways were upregulated. No significant changes could be detected in PYY3-36+liraglutide, liraglutide and PYY treated groups. Conclusions: Despite causing similar body weight changes compared to RYGB and BWM, PYY3-36+liraglutide treatment does not impact hypothalamic gene expression. Whether this striking difference is favorable or unfavorable to metabolic health in the long term requires further investigation.

2022-01-14 | GSE190218 | GEO

Bile diversion to the distal small intestine has comparable metabolic benefits to bariatric surgery

Project description:Roux-en-Y gastric bypass (RYGB) is highly effective in reversing obesity and associated diabetes. Recent observations in humans suggest a contributing role of increased circulating bile acids in mediating such effects. Here we use a diet-induced obesity mouse model and compared metabolic remission when bile flow was diverted through a gallbladder anastomosis to jejunum, ileum or duodenum (sham control). We found that only bile diversion to the ileum results in physiologic changes similar to RYGB including sustained improvements in weight, glucose tolerance and hepatic steatosis despite differential effects on hepatic gene expression. Circulating free fatty acids and triglycerides decrease while bile acids increase, particularly conjugated tauro-b-muricholic acid, an FXR antagonist. Activity of the hepatic FXR/FGF15 axis was reduced and associated with altered gut microbiota. Thus bile diversion, independent of surgical rearrangement of the gastrointestinal tract, imparts significant weight loss accompanied by improved glucose and lipid homeostasis that are hallmarks of RYGB. Total RNA from n = 5 DIO, n = 4 GB-IL, n = 5 RYGB mice livers was extracted of total RNA and submitted fro RNAseq

2015-05-13 | E-GEOD-68812 | biostudies-arrayexpress

Gastric bypass vs. ‘Medical Bypass’ - Impact on experimental diabetic kidney disease

Project description:Albuminuria is significantly reduced following Roux-en-Y gastric bypass (RYGB) surgery, suggesting a renoprotective effect of the intervention. Herein, we assess the relative impact of RYGB and RYGB equivalent non-surgical weight loss and glycaemic improvement on glomerular injury and global renal transcriptomic responses in the Zucker diabetic fatty rat (ZDF) model of diabetic nephropathy. We coined the term "medical bypass" (MB) to describe the intensive diet and pharmacotherapy based non-surgical intervention Adult ZDF rats underwent sham surgery (n=15) or RYGB (n=9). Nine sham-operated rats were calorie restricted and received insulin, liraglutide, metformin, ramipril, rosuvastatin and fenofibrate for 2 months (MB). Zucker fa/+ rats acted as healthy controls throughout. Bodyweight, glycaemia, albuminuria and glomerular injury specifically podocyte number, density and ultrastructure were assessed at follow up. Renal transcriptomes were compared by RNA-seq. RYGB resulted in 20-30% weight loss, normalized glycaemia and albuminuria and reduced indices of glomerular injury, specifically podocyte injury (foot process effacement). RYGB equivalent outcomes were obtained on all parameters following MB.

2019-07-10 | GSE117378 | GEO

Bile diversion to the distal small intestine has comparable metabolic benefits to bariatric surgery

2015-05-13 | GSE68812 | 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

Effects of RYGB on liver health in obese mice.

Project description:We investigated the effects of RYGB compared to a sham surgery or caloric restriction on hepatic function. For that, the goals of this study is to identify changes in the liver transcriptome profiling (RNA-seq) that could explain improvements in liver health and function with RYGB compared to other treatment methods.

2024-03-06 | GSE218026 | GEO

Transcription profiling of rats subjected to Roux-en-Y gastruc bypass to characterize of weight loss and weight regain mechanisms

Project description:Roux-en-Y gastric bypass (RYGB) is the most effective therapy for morbid obesity, but it has a ~20% failure rate. We used our established RYGB model in diet-induced obese (DIO) Sprague-Dawley rats, which reproduces human bi-phasic body weight (BW) loss pattern, to determine mechanisms contributing to success (RGYB-S) or failed (RYGB-F) RYGB. DIO rats were randomized to RYGB, sham operated Obese, and sham operated obese pair fed-linked to RYGB (PF) groups. BW, caloric intake (CI) and fecal output (FO) were recorded daily for 90 days, food efficiency (FE) was calculated, and morphologic changes were determined. Gut, adipose and thyroid hormones were measured in plasma. Mitochondrial respiratory complexes in skeletal muscle, expression of energy-related hypothalamic and fat peptides, receptors and enzymes were quantified. A 25% failure rate occurred. RYGB-S, RYGB-F and PF rats vs. Obese showed rapid BW decrease, followed by sustained BW loss in RYGB-S. RYGB-F and PF gradually increased BW. Expression profiling of both CNS (hypothalamus) and peripheral tissues (subcutaneous abdominal fat) strongly supported the involvement of a number of metabolic and feeding-related genes in the differential outcomes. Experiment Overall Design: 3 biological replicate RNA samples were prepared from 2 tissues (the subcutaneous abdominal fat or the hypothalamus) from rats in 3 treatment groups (rats losing weight successfully after gastric bypass surgery, rats gaining weight, and rats that were fed the same amount as the treated rats)

2008-06-16 | E-GEOD-8314 | biostudies-arrayexpress

Weight Loss after Roux-En Y Gastric Bypass Surgery Reveals Novel Skeletal Muscle Promoter-Specific DNA Methylation Changes in Obese Patients

Project description:The mechanisms of weight loss and metabolic improvements following bariatric surgery in skeletal muscle are not well known, however epigenetic modifications are likely to contribute. The aim of our study was to investigate skeletal muscle DNA methylation after weight loss induced by Roux-en-Y gastric bypass (RYGB) surgery.

2021-05-24 | GSE164305 | GEO

mRNA Seq of mouse tissues 9 days or 9 weeks after RYGB or sham surgery [9 days]

Project description:In this study we sought to characterize the acute response to RYGB surgery using diet induced obese mice. Controls were sham operated mice. Mice were age, sex, weight and diet matched.

2018-07-09 | GSE113821 | GEO

mRNA Seq of mouse tissues 9 weeks after RYGB or sham surgery [9 weeks]

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