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Identification of a human gut-derived LEAP2 fragment as a novel insulin secretagogue

ABSTRACT: The mechanisms underlying Roux-en-Y gastric bypass (RYGB) surgery-induced weight loss and the immediate postoperative beneficial metabolic effects associated with the operation remain uncertain. We aimed to identify novel gut-derived peptides with therapeutic potential in obesity and/or diabetes by determining genome-wide expression patterns in isolated human small intestinal enteroendocrine cells (EECs) obtained from 20 obese subjects undergoing RYGB and again three months later by upper enteroscopy. RYGB increased expression levels of the inverse ghrelin receptor agonist, liver-enriched antimicrobial peptide 2 (LEAP2), and a secreted endogenous LEAP2 fragment (LEAP238-47) demonstrated insulinotropic properties in vitro, promoting an increase in insulin release comparable to the gut hormone glucagon-like peptide 1. LEAP238-47 showed reciprocal effects on growth hormone secretagogue receptor (GHSR) activity, suggesting that the insulinotropic action of the peptide may be directly linked to attenuation of tonic GHSR activity. The fragment was infused to healthy human individuals, but compared to placebo, no glucoregulatory effect was observed in the chosen dose. In conclusion, small intestinal LEAP2 expression was upregulated after RYGB; and the fragment LEAP238-47 showed a strong in vitro insulinotropic effect, but failed to elicit glucoregulatory effects when infused in healthy human subjects.

ORGANISM(S): Homo sapiens

PROVIDER: GSE154306 | GEO | 2020/11/18

REPOSITORIES: GEO

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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

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

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

Project description: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.

2022-02-16 | GSE192425 | 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

Systems Signature Reveals Unique Remission-path of Diabetes Generated by Gastric Bypass Surgery

Project description:Gastric bypass surgery (GBP) emerging as a powerful tool for treatment of obesity has been applied for remission of diabetes. However, the GBP global molecular effects on diabetes remission independent of weight loss remain largely unknown. We profiled plasma metabolites and proteins of 10 normoglycemic obese (NO) and 9 diabetic obese (DO) patients at 1-week, 3-months and 1-year stages after Roux-en-Y gastric bypass (RYGB) as well pre-RYGB stage, by which 146 proteins and 128 metabolites were detected from both NO and DO groups at all four stages. By analyzing a set of bi-molecular associations among the corresponding network of the subjects with our newly developed computational method, we defined the representing physiological states (called the edge-states, in contrast to the traditional node-states) and the related molecular networks of NO and DO patients, respectively. The PCA results and hubnetworks of NO subjects were significantly different from those of DO patients; particularly, the hub-network rearrangement of both groups differentially went through after RYGB. In conclusion, by developing network-based systems signatures rather than relying on individual molecules, we for the first time reveal that RYGB generates a unique recovering-path for diabetes remission independent of weight loss.

2017-12-13 | PXD008071 | Pride

Intestinal microbiota after RYGB

Project description:Objective: Roux-Y gastric bypass (RYGB) surgery is a last treatment resort to induce substantial and sustained weight loss in severe obesity. The anatomical rearrangement affects the intestinal microbiota but so far, little information is available how it interferes with microbial functionality and microbial-host interaction independent from weight loss. Design: A RYGB rat model was utilized and compared to sham-operated controls which were kept at matched body weight as RYGB animals by food restriction. We assessed microbial taxonomy by 16S rRNA gene sequencing and functional activity by metaproteomics and metabolomics on microbiota samples collected separately from the ileum, the cecum as well as the colon and separately analysed the lumen and mucus associated microbiota. Results: Altered gut architecture in RYGB strongly affected the occurrence of Actinobacteria, especially Bifidobacteriaceae and Proteobacteria which were increased, whereas Firmicutes were decreased, although Streptococcaceae and Clostridium perfringens were observed at higher abundances. A decrease of conjugated as well as secondary bile acids was observed in the RYGB-gut lumen. In addition the arginine biosynthesis pathway in the microbiota was altered, indicated by the changes in abundance of upstream metabolites and enzymes, resulting in lower levels of arginine and higher levels of aspartate in the colon after RYGB. Conclusion: The anatomical rearrangement in RYGB affects microbiota composition and functionality by changes in amino acid and bile acid metabolism, independent of weight loss. The shift in microbiota taxonomic structure after RYGB may be mediated by the resulting change in composition of the bile acid pool in the gut lumen.

2020-03-17 | PXD013337 | Pride

Characterization of weight loss and weight regain mechanisms after Roux-en-Y gastric bypass in rats

2007-06-30 | GSE8314 | GEO

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

2015-05-13 | GSE68812 | GEO

Roux-en Y gastric bypass surgery induced genome-wide promoter specific changes in DNA methylation in whole blood of Obese patients

Project description:Twelve subjects were sampled before and six months after RYGB surgery to identify changes in the DNA methylation profile induced by the surgery. These changes were also compared to a reference methylome.

2014-12-31 | E-MTAB-3161 | biostudies-arrayexpress

High-throughput mediation analysis of human proteome and metabolome identifies mediators of post-bariatric surgical diabetes control

Project description:To improve the power of mediation in high-throughput studies, here we introduce High-throughput mediation analysis (Hitman), which accounts for direction of mediation and applies empirical Bayesian linear modeling. We apply Hitman in a retrospective, exploratory analysis of the SLIMM-T2D clinical trial in which participants with type 2 diabetes were randomized to Roux-en-Y gastric bypass (RYGB) or nonsurgical diabetes/weight management, and fasting plasma proteome and metabolome were assayed up to 3 years. RYGB caused greater improvement in HbA1c, which was mediated by growth hormone receptor (GHR). GHR’s mediation is more significant than clinical mediators, including BMI. GHR decreases at 3 months postoperatively alongside increased insulin-like growth factor binding proteins IGFBP1/BP2; plasma GH increased at 1 year. Experimental validation indicates (1) hepatic GHR expression decreases in post-bariatric rats; (2) GHR knockdown in primary hepatocytes decreases gluconeogenic gene expression and glucose production. Thus, RYGB may induce resistance to diabetogenic effects of GH signaling.

2021-08-24 | GSE122279 | GEO

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