Trans-omic analysis reveals allosteric and gene regulation-axes for altered glucose-responsive liver metabolism associated with obesity

Abstract

Impaired glucose tolerance associated with obesity causes postprandial hyperglycemia and can lead to type 2 diabetes. To study the differences in liver metabolism in the healthy and obese states, we constructed and analyzed trans-omic glucose-responsive metabolic networks with layers for metabolites, expression data for metabolic enzyme genes, transcription factors, 5 and insulin signaling proteins from the livers of healthy and obese mice. We integrated multiomic time-course data from wild-type (WT) and leptin-deficient obese (ob/ob) mice after orally administered glucose. In WT mice, metabolic reactions were rapidly regulated (within 10 minutes of oral glucose administration) primarily by glucose-responsive metabolites, especially ATP and NADP+, which functioned as allosteric regulators and substrates of metabolic enzymes, 10 and by Akt-dependent glucose-responsive genes encoding metabolic enzymes. In ob/ob mice, most rapid regulation by glucose-responsive metabolites was absent; instead, glucose administration produced slow changes in the expression of metabolic enzyme-encoding genes to alter metabolic reactions in a time scale of hours. Few common regulatory events occurred in both the healthy and obese mice. Thus, our trans-omic network analysis revealed regulation of 15 liver metabolism in response to glucose is mediated through different mechanisms in the healthy and obese states: Rapid changes in allosteric regulators and substrates and in gene expression dominate the healthy state, and slow transcriptional regulation dominates the obese state.One Sentence Summary: Rapid changes in regulatory metabolites and gene expression 20 dominate the healthy state, and slow transcriptional regulation dominates the obese state. Main Text:The ability to produce stable blood glucose is indispensable for human life and health (1-3). Although a large amount of glucose enters the body through meals, changes in organ metabolism 25 maintains glucose homeostasis (4-6). Impairment of the regulation of organ metabolism, commonly due to obesity and insulin resistance, results in hyperglycemia and development of type 2 diabetes mellitus (4-6). The liver, into which dietary glucose flows directly through the portal vein, has a primary function in maintaining glucose homeostasis (7,8). Indeed, the liver is both a glucose-producing organ, supplying glucose for extra-hepatic organs, and glucose-30 utilizing organ, metabolizing one third of orally administered glucose (8, 9). Oral intake of glucose produces drastic changes in the liver metabolism-not only glucose metabolism but also lipid and amino-acid metabolism, collectively glucose-responsive metabolism. The mechanisms regulating glucose-responsive metabolism in the liver and how these mechanisms are altered in obesity have yet to be identified. 35 Metabolism is a set of chemical reactions that convert one metabolite into another. Chemical reactions in metabolism, denoted here as metabolic reactions, involve metabolites, which function as substrates, products, and allosteri...