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

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

PROVIDER: PRJNA504526 | ENA |

REPOSITORIES: ENA

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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.

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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.Trial Registration: Clinicaltrials.gov NCT01073020.

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Project description:We adopted an omics (transcriptome, proteome, and metabolome) approach to characterize the differentially regulated molecules in mouse lens fiber cells exposed to cigarette smoke (CS). Eight pregnant female mice (gestation days 19-20) were placed in a smoking chamber that served as a CS-exposed group. The mothers and newborn pups were exposed to CS for five hours/day, five days/week for 110 days. In parallel, mice were kept in normal cages that served as a control group. The ocular lenses were isolated and fiber cells were separated from the lens epithelium under a microscope. The control and CS-exposed groups were maintained in four biological replicates each consisting of a pool of lens fiber cells from four eyes. The eight biological replicates (four control and four CS-exposed) of fiber cells were used for the next-generation-based transcriptome (RNA-Seq) sequencing, mass-spectrometry-based proteome, and metabolome profiling. RNA-Seq analysis identified the expression (≥1.0 FPKM) of 9,590 and 9,531 genes in control and CS-exposed fiber cells, respectively. The analysis identified 348 differentially expressed genes, which included 186 downregulated and 162 upregulated genes in CS-exposed fiber cells. Proteome profiling revealed a total of 2,424 proteins in control and CS-exposed fiber cells. Metabolome profiling identified a total of 280 metabolites, marked with decreased levels of branched-chain amino acids (BCAAs)-related metabolites in CS-exposed fiber cells. In conclusion, we have established a comprehensive omics profile of CS-exposed lens fiber cells. To the best of our knowledge, this is the first report investigating a comprehensive omics profile of CS-exposed fiber cells.

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