In vivo transomic analyses of glucose-responsive metabolism in skeletal muscle reveal core differences between the healthy and obese states

Abstract

Metabolic regulation in skeletal muscle is essential for blood glucose homeostasis. Obesity causes insulin resistance in skeletal muscle, leading to hyperglycemia and type 2 diabetes. In this study, we performed multiomic analysis of the skeletal muscle of wild-type (WT) and leptin-deficient obese (ob/ob) mice, and constructed regulatory transomic networks for metabolism after oral glucose administration. Our network revealed that metabolic regulation by glucose-responsive metabolites had a major effect on WT mice, especially carbohydrate metabolic pathways. By contrast, in ob/ob mice, much of the metabolic regulation by glucose-responsive metabolites was lost and metabolic regulation by glucose-responsive genes was largely increased, especially in carbohydrate and lipid metabolic pathways. We present some characteristic metabolic regulatory pathways found in central carbon, branched amino acids, and ketone body metabolism. Our transomic analysis will provide insights into how skeletal muscle responds to changes in blood glucose and how it fails to respond in obesity.

iTraNet: A Web-Based Platform for integrated Trans-Omics Network Visualization and Analysis

“…3E). In both the liver and muscle, more enzymes were influenced by mRNAs, while fewer enzymes were affected by metabolites in ob/ob , as previously described (11, 12). iTraNet also estimated the number of transporters associated with the mRNAs or metabolites or both (Fig.…”

“…4) using iTraNet. Both glucose administration (11, 12) and cold stimulation (31) affect various metabolites, including glucose and amino acid metabolism, but the regulation of these molecules and the overall topology of the networks might be different between the two conditions (Figs. 3, 4).…”

“…In this section, we summarize the approach that we followed to construct and analyze transomics networks and implement them as a web application. Further comprehensive details on the construction and analysis of trans-omics networks are available in our previous studies (3,(11)(12)(13)(14)(15)(16).…”

“…Upon input submission, iTraNet generated four types of biological networks and visualized the networks by arranging each metabolic pathway using the KEGG layout, as outlined in Figure 2. Since most visualization aspects have been previously discussed (11,12), we mainly present the outcomes of molecular estimations and network analyses. iTraNet also estimated TFs, miRNAs, enzymes, and transporters associated with the differentially expressed molecules (Fig.…”

“…In addition, intracellular processes interact with extracellular molecules via transporters. These rationales underscore the importance of applying multilayered trans-omics networks to understanding biological systems; we have applied this approach to understanding metabolism in living systems (3,(11)(12)(13)(14)(15)(16).…”