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Multi-omic network-based interrogation of rat liver metabolism following gastric bypass surgery featuring SWATH proteomics.

ABSTRACT: Morbidly obese patients often elect for Roux-en-Y gastric bypass (RYGB), a form of bariatric surgery that triggers a remarkable 30% reduction in excess body weight and reversal of insulin resistance for those who are type II diabetic. A more complete understanding of the underlying molecular mechanisms that drive the complex metabolic reprogramming post-RYGB could lead to innovative non-invasive therapeutics that mimic the beneficial effects of the surgery, namely weight loss, achievement of glycemic control, or reversal of non-alcoholic steatohepatitis (NASH). To facilitate these discoveries, we hereby demonstrate the first multi-omic interrogation of a rodent RYGB model to reveal tissue-specific pathway modules implicated in the control of body weight regulation and energy homeostasis. In this study, we focus on and evaluate liver metabolism three months following RYGB in rats using both SWATH proteomics, a burgeoning label free approach using high resolution mass spectrometry to quantify protein levels in biological samples, as well as MRM metabolomics. The SWATH analysis enabled the quantification of 1378 proteins in liver tissue extracts, of which we report the significant down-regulation of Thrsp and Acot13 in RYGB as putative targets of lipid metabolism for weight loss. Furthermore, we develop a computational graph-based metabolic network module detection algorithm for the discovery of non-canonical pathways, or sub-networks, enriched with significantly elevated or depleted metabolites and proteins in RYGB-treated rat livers. The analysis revealed a network connection between the depleted protein Baat and the depleted metabolite taurine, corroborating the clinical observation that taurine-conjugated bile acid levels are perturbed post-RYGB.

SUBMITTER: Sridharan GV

PROVIDER: S-EPMC5956888 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Multi-omic network-based interrogation of rat liver metabolism following gastric bypass surgery featuring SWATH proteomics.

Sridharan Gautham Vivek GV D'Alessandro Matthew M Bale Shyam Sundhar SS Bhagat Vicky V Gagnon Hugo H Asara John M JM Uygun Korkut K Yarmush Martin L ML Saeidi Nima N

Technology 20170926 3

Morbidly obese patients often elect for Roux-en-Y gastric bypass (RYGB), a form of bariatric surgery that triggers a remarkable 30% reduction in excess body weight and reversal of insulin resistance for those who are type II diabetic. A more complete understanding of the underlying molecular mechanisms that drive the complex metabolic reprogramming post-RYGB could lead to innovative non-invasive therapeutics that mimic the beneficial effects of the surgery, namely weight loss, achievement of gly ...[more]

PMID: 29780857

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Project description:Roux-en Y gastric bypass (RYGB) surgery is an effective treatment for obesity; however, it may negatively impact skeletal health by increasing fracture risk. This increase may be the result not only of decreased bone mineral density but also of changes in bone microstructure, for example, increased cortical porosity. Increased tibial and radial cortical porosity of patients undergoing RYGB surgery has been observed as early as 6 months postoperatively; however, local microstructural changes and associated biological mechanisms driving this increase remain unclear. To provide insight, we studied the spatial distribution of cortical porosity in 42 women and men (aged 46 ± 12 years) after RYGB surgery. Distal tibias and radii were evaluated with high-resolution peripheral quantitative computed tomography (HR-pQCT) preoperatively and at 12 months postoperatively. Laminar analysis was used to determine cortical pore number and size within the endosteal, midcortical, and periosteal layers of the cortex. Paired t tests were used to compare baseline versus follow-up porosity parameters in each layer. Mixed models were used to compare longitudinal changes in laminar analysis outcomes between layers. We found that the midcortical (0.927 ± 0.607 mm-2 to 1.069 ± 0.654 mm-2 , p = 0.004; 0.439 ± 0.293 mm-2 to 0.509 ± 0.343 mm-2 , p = 0.03) and periosteal (0.642 ± 0.412 mm-2 to 0.843 ± 0.452 mm-2 , p < 0.0001; 0.171 ± 0.101 mm-2 to 0.230 ± 0.160 mm-2 , p = 0.003) layers underwent the greatest increases in porosity over the 12-month period at the distal tibia and radius, respectively. The endosteal layer, which had the greatest porosity at baseline, did not undergo significant porosity increase over the same period (1.234 ± 0.402 mm-2 to 1.259 ± 0.413 mm-2 , p = 0.49; 0.584 ± 0.290 mm-2 to 0.620 ± 0.299 mm-2 , p = 0.35) at the distal tibia and radius, respectively. An alternative baseline-mapping approach for endosteal boundary definition confirmed that cortical bone loss was not primarily endosteal. These findings indicate that increases in cortical porosity happen in regions distant from the endosteal surface, suggesting that the underlying mechanism driving the increase in cortical porosity is not merely endosteal trabecularization. © 2022 American Society for Bone and Mineral Research (ASBMR).

Project description:BackgroundLack of robust research methodology for assessing ingestive behavior has impeded clarification of the mediators of food intake following gastric bypass (GBP) surgery.ObjectivesTo evaluate changes in directly measured 24-h energy intake (EI), energy density (ED) (primary outcomes), eating patterns, and food preferences (secondary outcomes) in patients and time-matched weight-stable comparator participants.MethodsPatients [n = 31, 77% female, BMI (in kg/m2) 45.5 ± 1.3] and comparators (n = 32, 47% female, BMI 27.2 ± 0.8) were assessed for 36 h under fully residential conditions at baseline (1 mo presurgery) and at 3 and 12 mo postsurgery. Participants had ad libitum access to a personalized menu (n = 54 foods) based on a 6-macronutrient mix paradigm. Food preferences were assessed by the Leeds Food Preference Questionnaire. Body composition was measured by whole-body DXA.ResultsIn the comparator group, there was an increase in relative fat intake at 3 mo postsurgery; otherwise, no changes were observed in food intake or body composition. At 12 mo postsurgery, patients lost 27.7 ± 1.6% of initial body weight (P < 0.001). The decline in EI at 3 mo postsurgery (-44% from baseline, P < 0.001) was followed by a partial rebound at 12 mo (-18% from baseline), but at both times, dietary ED and relative macronutrient intake remained constant. The decline in EI was due to eating the same foods as consumed presurgery and by decreasing the size (g, MJ), but not the number, of eating occasions. In patients, reduction in explicit liking at 3 mo (-11.56 ± 4.67, P = 0.007) and implicit wanting at 3 (-15.75 ± 7.76, P = 0.01) and 12 mo (-15.18 ± 6.52, P = 0.022) for sweet foods were not matched by reduced intake of these foods. Patients with the greatest reduction in ED postsurgery reduced both EI and preference for sweet foods.ConclusionsAfter GBP, patients continue to eat the same foods but in smaller amounts. These findings challenge prevailing views about the dynamics of food intake following GBP surgery. This trial was registered as clinicaltrials.gov as NCT03113305.

Dataset Information

Multi-omic network-based interrogation of rat liver metabolism following gastric bypass surgery featuring SWATH proteomics.

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Multi-omic network-based interrogation of rat liver metabolism following gastric bypass surgery featuring SWATH proteomics.

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