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Transomics analysis reveals allosteric and gene regulation axes for altered hepatic glucose-responsive metabolism in obesity

Obesity shifts glucose-responsive hepatic metabolism from rapid regulation by metabolites to slower changes in gene expression. A regulatory switch in obesity The liver not only produces glucose, it also consumes a large amount of glucose, making this organ critical for glucose homeostasis. To understand how obesity alters glucose-responsive metabolism in the liver, Kokaji et al. performed multiomics analyses on the livers and blood of normal or ob/ob mice, a genetic model for obesity. The authors next reconstructed the glucose-sensitive biochemical network that encompassed metabolites, metabolic reactions, metabolic enzymes, transcription factors, and proteins in the insulin signaling pathway in both normal and ob/ob mice. Their analysis suggested that whereas normal hepatic metabolic responses to glucose were rapid and relied on regulation by metabolites, those in ob/ob mice were slow and depended on changes in gene expression. The authors note that their data imply that obesity not only slows hepatic metabolic responses to glucose, but also makes these responses more energy-consuming (through phosphorylation of enzymes and transcription factors and through gene expression changes) and less precise (due to the slowness and nature of the responses). Impaired glucose tolerance associated with obesity causes postprandial hyperglycemia and can lead to type 2 diabetes. To study the differences in liver metabolism in healthy and obese states, we constructed and analyzed transomics glucose-responsive metabolic networks with layers for metabolites, expression data for metabolic enzyme genes, transcription factors, and insulin signaling proteins from the livers of healthy and obese mice. We integrated multiomics time course data from wild-type and leptin-deficient obese (ob/ob) mice after orally administered glucose. In wild-type mice, metabolic reactions were rapidly regulated within 10 min of oral glucose administration by glucose-responsive metabolites, which functioned as allosteric regulators and substrates of metabolic enzymes, and by Akt-induced changes in the expression of glucose-responsive genes encoding metabolic enzymes. In ob/ob mice, the majority of rapid regulation by glucose-responsive metabolites was absent. Instead, glucose administration produced slow changes in the expression of carbohydrate, lipid, and amino acid metabolic enzyme–encoding genes to alter metabolic reactions on a time scale of hours. Few regulatory events occurred in both healthy and obese mice. Thus, our transomics network analysis revealed that regulation of glucose-responsive liver metabolism is mediated through different mechanisms in healthy and obese states. Rapid changes in allosteric regulators and substrates and in gene expression dominate the healthy state, whereas slow changes in gene expression dominate the obese state.