Integrated Network Analysis Reveals an Association between Plasma Mannose Levels and Insulin Resistance

• Published in: Cell metabolism Vol. 24; no. 1; pp. 172 - 184
• Main Authors: Lee, Sunjae, Zhang, Cheng, Kilicarslan, Murat, Piening, Brian D., Bjornson, Elias, Hallström, Björn M., Groen, Albert K., Ferrannini, Ele, Laakso, Markku, Snyder, Michael, Blüher, Matthias, Uhlen, Mathias, Nielsen, Jens, Smith, Ulf, Serlie, Mireille J., Boren, Jan, Mardinoglu, Adil
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.07.2016
• Subjects: Adipose-Tissue; Adult; Amino-Acid; Bariatric Surgery; Case-Control Studies; Cell Biology; Cellbiologi; Endocrinology & Metabolism; Endocrinology and Diabetes; Endokrinologi och diabetes; Female; Fructose - metabolism; Gene Expression Profiling; Gene Regulatory Networks; Genome-Scale; genome-scale metabolic models; Glucose-Tolerance; Humans; Insulin - metabolism; Insulin Resistance; Insulin Secretion; Liver; Male; mannose; Mannose - blood; metabolic; Metabolic Network; Metabolic Networks and Pathways; N-Glycosylation; network; obesity; Obesity - blood; Protein Interaction Maps; Protein Interaction Networks; protein-protein interaction networks; Proteomics; Sensitivity; transcriptional regulatory networks; genome-scale metabolic models; mannose; protein-protein interaction networks; transcriptional regulatory networks; insulin resistance; obesity
• ISSN: 1550-4131; 1932-7420; 1932-7420
• DOI: 10.1016/j.cmet.2016.05.026

To investigate the biological processes that are altered in obese subjects, we generated cell-specific integrated networks (INs) by merging genome-scale metabolic, transcriptional regulatory and protein-protein interaction networks. We performed genome-wide transcriptomics analysis to determine the global gene expression changes in the liver and three adipose tissues from obese subjects undergoing bariatric surgery and integrated these data into the cell-specific INs. We found dysregulations in mannose metabolism in obese subjects and validated our predictions by detecting mannose levels in the plasma of the lean and obese subjects. We observed significant correlations between plasma mannose levels, BMI, and insulin resistance (IR). We also measured plasma mannose levels of the subjects in two additional different cohorts and observed that an increased plasma mannose level was associated with IR and insulin secretion. We finally identified mannose as one of the best plasma metabolites in explaining the variance in obesity-independent IR. [Display omitted] •We generated cell-specific integrated networks for lean and obese subjects•We found dysregulations in the mannose metabolism in obese subjects•Plasma mannose level was associated with insulin resistance independent of BMI•Mannose is used in explaining the variance in obesity-independent insulin resistance Lee et al. merged genome-scale metabolic models (GEMs), transcriptional regulatory networks (TRNs), and protein-protein interaction networks (PPINs) to generate cell-specific integrated networks for hepatocytes, myocytes, and adipocytes of lean and obese subjects undergoing bariatric surgery. They identified, and independently validated, plasma mannose as highly associated with insulin resistance, independent of BMI.