A multicenter in vivo Japanese "transomics" analysis led by scientists at the University of Tokyo (UT) has revealed previously unknown allosteric and genetic regulatory axes underlying the altered hepatic glucose-responsive metabolism seen in obesity.
This discovery provides key insights into how obesity moves the regulatory blood glucose profile away from rapid regulation by metabolites toward that by slower gene expression, the authors reported in the December 1, 2020, edition of Science Signaling.
This switch from rapid to slow control of blood glucose may have important implications for the future management of metabolic disorders including obesity, insulin resistance and type 2 diabetes, the global incidence of which is increasing.
For example, "we discovered that most of the fast allosteric regulation by metabolites was lost in the obese state in mice," said study leader Shinya Kuroda, a professor in the Department of Biological Sciences of the Graduate School of Science at UT.
Therefore, "reactivation of the regulatory [glucose control] mechanism might alleviate the postprandial hyperglycemia seen in obesity," Kuroda told BioWorld Science.
Most glucose is derived from digested food, but changes in organ metabolism maintain glucose homeostasis, with impaired metabolic regulation due to obesity and insulin resistance resulting in hyperglycemia and type 2 diabetes.
Maintaining glucose homeostasis is the primary function of the liver, which supplies glucose for other organs and metabolizes one-third of orally administered glucose.
Oral glucose intake changes hepatic glucose, lipid and amino acid metabolism, collectively termed glucose-responsive metabolism, but the mechanisms regulating this and how they change in obesity remain unclear.
Metabolites function as substrates, products and allosteric regulators of enzymes catalyzing metabolic reactions, which are also regulated by cellular processes affecting the amount of enzyme, such as gene expression changes or post-translational enzymatic modifications e.g., phosphorylation.
Metabolic reactions are thus regulated by a network comprising metabolites, metabolic enzymes and their phosphorylation status, transcription factors and their activation, and by signaling pathways mediating metabolic enzyme phosphorylation and transcription factors.
Therefore, mechanisms regulating hepatic metabolic reactions and obesity-associated changes could be assessed by integrating measurements of metabolites, gene expression and phosphorylation status of metabolic enzymes and transcription factors, and the amount and activation of signaling molecules into a complex transomics network.
Metabolomic, transcriptomic and proteomic analyses enable large-scale molecular measurement in a multiomics network, using simultaneously measured multiomics data based on direct molecular interactions.
This approach has been used to construct an insulin-induced metabolic regulatory transomics network in a rat hepatoma cell line, by integrating simultaneous multiomics measurements, which showed selective regulation of the network dependent on the insulin dose.
However, the regulatory transomics network for glucose-responsive hepatic metabolic reactions and obesity-associated alterations in this regulatory network has remained unidentified.
In the new study, the researchers constructed regulatory transomics networks for hepatic glucose-responsive-metabolic reactions to reveal the global regulatory mechanisms controlling glucose metabolism in both health and obesity, using wild-type (WT) and (ob/ob) mouse models of obesity and insulin resistance.
"The ob/ob mice are a widely used model of obesity and insulin resistance, because they become obese by overeating due to deficiency of the anorexigenic hormone, leptin," noted Kuroda.
The researchers then simultaneously measured multiomics data from normal or obese mouse models given glucose orally and integrated these data into a transomics network.
In WT mice, glucose-responsive metabolic reactions were rapidly regulated within 10 minutes of oral glucose administration by glucose-responsive metabolites, which functioned as allosteric regulators and substrates of metabolic enzymes, and by Akt-induced changes in expression of glucose-responsive genes encoding metabolic enzymes.
Conversely, in ob/ob mice, glucose administration elicited slower changes in expression of carbohydrate, lipid and amino acid metabolic enzyme-encoding genes to alter metabolic reactions over several hours.
These findings cast some light on the relationship between obesity and diabetes. "Our results showed slow transcriptional regulation in obese mice, including activation of lipid synthesis, which suggests accelerated lipid accumulation in the livers of obese mice," said Kuroda. These findings showed that rapid changes in allosteric regulators and substrates and in gene expression dominated the healthy state, whereas slower changes in gene expression predominated in obesity.
Regarding new drug development, "the recovery of the regulatory glucose metabolism lost in obese mice might contribute to the development of novel drug treatments for hyperglycemia," Kuroda said.
Looking ahead, he said, "to reveal how closely our mouse findings might reflect those in humans, we are now comparing identified transomics networks with human data, such as those from genome-wide associated studies.
"We are also planning in future to research glucose-responsiveness in other organs related to carbohydrate metabolism, such as muscle."