In vivo and in silico dynamics of the development of Metabolic Syndrome

PLoS Comput Biol. 2018 Jun 7;14(6):e1006145. doi: 10.1371/journal.pcbi.1006145. eCollection 2018 Jun.

Abstract

The Metabolic Syndrome (MetS) is a complex, multifactorial disorder that develops slowly over time presenting itself with large differences among MetS patients. We applied a systems biology approach to describe and predict the onset and progressive development of MetS, in a study that combined in vivo and in silico models. A new data-driven, physiological model (MINGLeD: Model INtegrating Glucose and Lipid Dynamics) was developed, describing glucose, lipid and cholesterol metabolism. Since classic kinetic models cannot describe slowly progressing disorders, a simulation method (ADAPT) was used to describe longitudinal dynamics and to predict metabolic concentrations and fluxes. This approach yielded a novel model that can describe long-term MetS development and progression. This model was integrated with longitudinal in vivo data that was obtained from male APOE*3-Leiden.CETP mice fed a high-fat, high-cholesterol diet for three months and that developed MetS as reflected by classical symptoms including obesity and glucose intolerance. Two distinct subgroups were identified: those who developed dyslipidemia, and those who did not. The combination of MINGLeD with ADAPT could correctly predict both phenotypes, without making any prior assumptions about changes in kinetic rates or metabolic regulation. Modeling and flux trajectory analysis revealed that differences in liver fluxes and dietary cholesterol absorption could explain this occurrence of the two different phenotypes. In individual mice with dyslipidemia dietary cholesterol absorption and hepatic turnover of metabolites, including lipid fluxes, were higher compared to those without dyslipidemia. Predicted differences were also observed in gene expression data, and consistent with the emergence of insulin resistance and hepatic steatosis, two well-known MetS co-morbidities. Whereas MINGLeD specifically models the metabolic derangements underlying MetS, the simulation method ADAPT is generic and can be applied to other diseases where dynamic modeling and longitudinal data are available.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Computational Biology / methods*
  • Computer Simulation*
  • Diet, High-Fat
  • Disease Models, Animal
  • Humans
  • Insulin Resistance
  • Lipid Metabolism
  • Metabolic Syndrome / metabolism*
  • Metabolic Syndrome / physiopathology*
  • Mice
  • Models, Biological*

Grant support

This study was supported by the European Union’s Research and Innovation programme (https://ec.europa.eu/research/health/index.cfm); grant FP7-HEALTH-305707: “A systems biology approach to RESOLVE the molecular pathology of two hallmarks of patients with metabolic syndrome and its co-morbidities; hypertriglyceridemia and low HDL-cholesterol”. YW is supported by a VENI grant from NWO-ZonMW (91617027). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.