An integrative model of cardiometabolic traits identifies two types of metabolic syndrome
- Tel Aviv University, Israel
- Radboud University Medical Center, Netherlands
- University of Medicine and Pharmacy, Romania
Abstract
Human diseases arise in a complex ecosystem composed of disease mechanisms and the whole-body state. However, the precise nature of the whole-body state and its relations with disease remain obscure. Here we map similarities among clinical parameters in normal physiological settings, including a large collection of metabolic, hemodynamic and immune parameters, and then use the mapping to dissect phenotypic states. We find that the whole-body state is faithfully represented by a quantitative two-dimensional model. One component of the whole-body state represents 'metabolic syndrome' (MetS) – a conventional way to determine the cardiometabolic state. The second component is decoupled from the classical MetS, suggesting a novel 'non-classical MetS' that is characterized by dozens of parameters, including dysregulated lipoprotein parameters (e.g. high LDL- cholesterol and low free cholesterol in small HDL particles) and attenuated cytokine responses of PBMCs to ex vivo stimulations. Both components are associated with disease, but differ in their particular associations, thus opening new avenues for improved personalized diagnosis and treatment. These results provide a practical paradigm to describe whole-body states and to dissect complex disease within the ecosystem of the human body.
Data availability
Both the obesity cohort and the normal BMI cohort were part of the Human Functional Genomics Project (www.humanfunctionalgenomics.org) and has been previously published.The coronary-atherosclerosis cohort was collected as part of the HORIZON 2020 European Research Program - "REPROGRAM: Targeting epigenetic REPROGRamming of innate immune cells in Atherosclerosis Management and other chronic inflammatory diseases".SLE sequencing public datasets used in our analysis: GSE65391, GSE49454.
Article and author information
Author details
Niels Peter Riksen
Funding
European Commission (637885)
- Amit Frishberg
- Irit Gat-Viks
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Edward D Janus, University of Melbourne, Australia
Version history
- Received: August 2, 2020
- Accepted: January 27, 2021
- Accepted Manuscript published: January 28, 2021 (version 1)
- Version of Record published: February 25, 2021 (version 2)
Copyright
© 2021, Frishberg et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
Metrics
-
- 2,157
- views
-
- 231
- downloads
-
- 4
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
An integrative model of cardiometabolic traits identifies two types of metabolic syndrome
eLife 10:e61710.
https://doi.org/10.7554/eLife.61710
Further reading
-
- Cell Biology
- Computational and Systems Biology
Bats have unique characteristics compared to other mammals, including increased longevity and higher resistance to cancer and infectious disease. While previous studies have analyzed the metabolic requirements for flight, it is still unclear how bat metabolism supports these unique features, and no study has integrated metabolomics, transcriptomics, and proteomics to characterize bat metabolism. In this work, we performed a multi-omics data analysis using a computational model of metabolic fluxes to identify fundamental differences in central metabolism between primary lung fibroblast cell lines from the black flying fox fruit bat (Pteropus alecto) and human. Bat cells showed higher expression levels of Complex I components of electron transport chain (ETC), but, remarkably, a lower rate of oxygen consumption. Computational modeling interpreted these results as indicating that Complex II activity may be low or reversed, similar to an ischemic state. An ischemic-like state of bats was also supported by decreased levels of central metabolites and increased ratios of succinate to fumarate in bat cells. Ischemic states tend to produce reactive oxygen species (ROS), which would be incompatible with the longevity of bats. However, bat cells had higher antioxidant reservoirs (higher total glutathione and higher ratio of NADPH to NADP) despite higher mitochondrial ROS levels. In addition, bat cells were more resistant to glucose deprivation and had increased resistance to ferroptosis, one of the characteristics of which is oxidative stress. Thus, our studies revealed distinct differences in the ETC regulation and metabolic stress responses between human and bat cells.
-
- Computational and Systems Biology
- Neuroscience
Normal aging leads to myelin alterations in the rhesus monkey dorsolateral prefrontal cortex (dlPFC), which are positively correlated with degree of cognitive impairment. It is hypothesized that remyelination with shorter and thinner myelin sheaths partially compensates for myelin degradation, but computational modeling has not yet explored these two phenomena together systematically. Here, we used a two-pronged modeling approach to determine how age-related myelin changes affect a core cognitive function: spatial working memory. First, we built a multicompartment pyramidal neuron model fit to monkey dlPFC empirical data, with an axon including myelinated segments having paranodes, juxtaparanodes, internodes, and tight junctions. This model was used to quantify conduction velocity (CV) changes and action potential (AP) failures after demyelination and subsequent remyelination. Next, we incorporated the single neuron results into a spiking neural network model of working memory. While complete remyelination nearly recovered axonal transmission and network function to unperturbed levels, our models predict that biologically plausible levels of myelin dystrophy, if uncompensated by other factors, can account for substantial working memory impairment with aging. The present computational study unites empirical data from ultrastructure up to behavior during normal aging, and has broader implications for many demyelinating conditions, such as multiple sclerosis or schizophrenia.
