Roux‐en‐Y gastric bypass surgery alters serum metabolites and fatty acids in patients with morbid obesity

Wijayatunga, Nadeeja; Sams, Valerie G.; Dawson, John A.; Mancini, Matthew; Mancini, Gregory J.; Moustaid‐Moussa, Naima

doi:10.1002/dmrr.3045

Cited by 46 publications

(43 citation statements)

References 62 publications

(150 reference statements)

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“…There were robust post-RYGB decreases in BCAA and multiple downstream catabolic intermediates, including C3 and C5 acylcarnitines, with isovalerylcarnitine as a putative causal metabolite mediator. Our results are consistent with prior findings of increased BCAA in insulin resistance (65,66) and reduced BCAA in response to RYGB in nonrandomized studies (25)(26)(27). Lower BCAA levels post-RYGB may be a consequence of weight loss-linked improvements in insulin sensitivity or altered microbial metabolism (34), but may also contribute directly to improved insulin sensitivity (67).…”

Section: Discussionsupporting

confidence: 91%

“…However, preclinical studies indicate incretins are not required for beneficial effects of bariatric procedures (20)(21)(22)(23)(24). Other postoperative changes include reductions in branched chain amino acids (BCAA) (25)(26)(27) and aromatic amino acids (28), alterations in plasma bile acids and FXR signaling (29)(30)(31) and in other hormones (32). RYGB alters the microbiome community composition toward that of less obese individuals (33), with increased abundance of many amino acid fermenters (34).…”

Section: Introductionmentioning

confidence: 99%

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Novel mediation analysis of human plasma proteome and metabolome reveals mediators of improved glycemia after gastric bypass surgery

Dreyfuss

Yuchi

Hui

et al. 2019

Preprint

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Molecular mechanisms by which Roux-en-Y gastric bypass (RYGB) improves glycemic control and metabolism in type 2 diabetes (T2D) remain incompletely understood. In the SLIMM-T2D trial, participants with T2D were randomized to RYGB or nonsurgical management and their fasting plasma proteome and metabolome were analyzed for up to 3 years. To identify analytes that mediate improvement in outcomes, we developed a high-throughput mediation analysis method (Hitman), which is significantly more powerful than existing methods. Top-ranking analyte mediators of glycemia improvement were growth hormone receptor and prolylhydroxyproline, which were more significant than any clinical mediator, including BMI. Betaalanine and Histidine Metabolism (both including CNDP1) were top differentially regulated pathways, and Valine, Leucine and Isoleucine Degradation was also a top differentiallyregulated pathway and a top mediator of improvement in insulin resistance. The identified analytes may serve as novel targets for T2D therapy. More broadly, Hitman can identify analyte mediators of outcomes in randomized trials for which high-throughput data are available. Results ClinicalProteomic and metabolomic data at baseline, the 3 month time point, and 1 year were available from 35 of the 38 SLIMM-T2D participants. Metabolic characteristics of these 35 participants did not differ between groups at baseline ( Table S1). The HbA1c and BMI of those that had proteomics or metabolomics per time point also did not differ from the SLIMM-T2D participants within their group at any time point (Figure S1). After 3 years, no DWM participants achieved study-defined glycemic goals (HbA1c<6.5% and fasting plasma glucose<126 mg/dL), whereas eight RYGB participants did, and seven of these eight participants were not receiving any antidiabetes medications (Simonson et al., 2018). The number of participants taking each diabetes medication class per arm at each time point is tabulated in Table S1. ProteomeFasting proteomics were profiled at baseline, the 3 month time point, and years 1, 2 and 3 in RYGB and DWM. At baseline (pre-randomization), there were no statistically significant proteins as assessed by false discovery rate (FDR<0.15). For later, post-randomization time points, reduction in BMI was greater in RYGB, so groups were compared both with and without adjustment for each person's BMI change. Differences in the baseline-corrected proteome in RYGB vs. DWM (i.e. differences between groups in changes over time) emerged at the 3 month time point, with 14 significant proteins in the unadjusted analysis and 8 in the BMI-adjusted analysis. Proteins common to both analyses and downregulated in RYGB were: carnosine dipeptidase 1 (CNDP1, also known as Beta-Ala-His dipeptidase 1) and Fetuin-B (FETUB). Proteins in common upregulated in RYGB were: integrin-binding sialoprotein (IBSP), insulin-like growth factor binding protein (IGFBP2), endothelial cell-specific molecule 1 (ESM1), macrophage metalloelastase (MMP12), alpha-1-antichymotrypsin complex (SERPINA3), ...

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Section: Discussionsupporting

confidence: 91%

Section: Introductionmentioning

confidence: 99%

Novel mediation analysis of human plasma proteome and metabolome reveals mediators of improved glycemia after gastric bypass surgery

Dreyfuss

Yuchi

Hui

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Numerous clinical studies have shown that bariatric surgery reduces the circulating BCAA levels (18)(19)(20)(21)28). The objective of our study was to answer whether improved BCAA homeostasis is necessary for the metabolic improvements after VSG.…”

Section: Discussionmentioning

confidence: 98%

“…Vertical Sleeve Gastrectomy (VSG), have proven to be among the best treatments for weight loss and T2D (17). Recent studies also showed that bariatric surgery significantly reduces circulating BCAA levels post-surgery and BCAA levels remain lower at 2 years post operatively (18)(19)(20). These effective surgical interventions not only lead to decreased circulating BCAA levels, but also have been shown to improve BCAA catabolism, specifically in adipose tissue (21,22).…”

Section: Although Invasive Weight Loss Surgeries Such As Roux-en-y Gmentioning

confidence: 99%

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The role of elevated branched chain amino acids in the potent effects of vertical sleeve gastrectomy to reduce weight and improve glucose regulation in mice

Bozadjieva-Kramer

Evers

Shin

et al. 2020

Preprint

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Obesity and type 2 diabetes mellitus (T2D) are growing epidemics resulting in increased morbidity and mortality. An emerging body of evidence has shown that elevated levels of branched-chain amino acids (BCAA) and their metabolites are strongly positively associated with obesity, insulin-resistance and T2D. Bariatric surgery is among the best treatments for weight loss and the alleviation of T2D. Additionally, clinical studies have reported that bariatric surgery decreases the circulating levels of BCAA. The objective of these studies was to test the hypothesis that reduced BCAA levels contribute to the metabolic improvements after VSG. We find that, as in humans, circulating BCAA levels are significantly lower in VSG rats and mice compared to Sham controls. In order to increase circulating BCAA levels, we tested mice with either increased dietary intake of BCAA or impaired BCAA catabolism by total body deletion of mitochondrial phosphatase 2C, Pp2cm, a key enzyme in the rate-limiting step in BCAA catabolism. Our results show that a decrease in circulating BCAA levels is not necessary for sustained body weight loss and improved glucose tolerance after VSG. While it is clear that circulating levels of BCAAs are excellent biomarkers for metabolic status, the current data do not support a causal role in determining metabolic regulation and the response to VSG.

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Roux‐en‐Y gastric bypass surgery alters serum metabolites and fatty acids in patients with morbid obesity

Wijayatunga

Sams

Dawson

et al. 2018

Diabetes Metabolism Res

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AimBariatric surgery induces significant weight loss, increases insulin sensitivity, and reduces mortality, but the underlying mechanisms are not clear. It was hypothesized that Roux‐en‐Y gastric bypass (RYGB) surgery improves metabolic profile along with weight loss. The objective of this pilot study was to evaluate changes in serum metabolites and fatty acids (FA) at 2 weeks and 6 months after RYGB.Materials and MethodsSerum samples were collected pre‐surgery, at 2 weeks and 6 months post‐surgery from 20 patients undergoing RYGB surgery. Serum non‐esterified free FA (NEFA) were measured. Serum metabolites and FA were measured using nuclear magnetic resonance spectroscopy and improved direct fatty acid methyl ester synthesis and the gas chromatography/mass spectrometry method, respectively, in subjects who completed follow‐up at 6 months (n = 8).ResultsMean (standard deviation) percent total weight loss was 6.70% (1.7) and 24.91% (6.63) at 2 weeks (n = 15) and 6 months (n = 8) post‐surgery, respectively. NEFA were significantly reduced at 6 months post‐surgery (P = 0.001, n = 8). Serum branched chain amino acids, 2‐aminobutyrate, butyrate, 2‐hydroxybutyrate, 3‐hydroxybutyrate, acetone, 2‐methylglutarate, and 2‐oxoisocaproate were significantly reduced, while serum alanine, glycine, pyruvate, and taurine were significantly elevated at 6 months post‐surgery compared with pre‐surgery (n = 8, P < 0.05). Also, serum FA C10:0, C13:0, C14:0, C15:0, and C18:0 increased significantly (n = 8, P < 0.05) by 6 months post‐surgery.ConclusionsChanges in serum metabolites and FA at 6 months post‐RYGB surgery in this pilot study with limited number of participants are suggestive of metabolic improvement; larger studies are warranted for confirmation.

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Roux‐en‐Y gastric bypass surgery alters serum metabolites and fatty acids in patients with morbid obesity

Cited by 46 publications

References 62 publications

Novel mediation analysis of human plasma proteome and metabolome reveals mediators of improved glycemia after gastric bypass surgery

Novel mediation analysis of human plasma proteome and metabolome reveals mediators of improved glycemia after gastric bypass surgery

The role of elevated branched chain amino acids in the potent effects of vertical sleeve gastrectomy to reduce weight and improve glucose regulation in mice

Roux‐en‐Y gastric bypass surgery alters serum metabolites and fatty acids in patients with morbid obesity

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