A network-based approach to identify deregulated pathways and drug effects in metabolic syndrome

Nat Commun. 2019 Nov 18;10(1):5215. doi: 10.1038/s41467-019-13208-z.


Metabolic syndrome is a pathological condition characterized by obesity, hyperglycemia, hypertension, elevated levels of triglycerides and low levels of high-density lipoprotein cholesterol that increase cardiovascular disease risk and type 2 diabetes. Although numerous predisposing genetic risk factors have been identified, the biological mechanisms underlying this complex phenotype are not fully elucidated. Here we introduce a systems biology approach based on network analysis to investigate deregulated biological processes and subsequently identify drug repurposing candidates. A proximity score describing the interaction between drugs and pathways is defined by combining topological and functional similarities. The results of this computational framework highlight a prominent role of the immune system in metabolic syndrome and suggest a potential use of the BTK inhibitor ibrutinib as a novel pharmacological treatment. An experimental validation using a high fat diet-induced obesity model in zebrafish larvae shows the effectiveness of ibrutinib in lowering the inflammatory load due to macrophage accumulation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenine / analogs & derivatives
  • Animals
  • Diet, High-Fat
  • Drug Repositioning
  • Gene Regulatory Networks* / drug effects
  • Humans
  • Lipid Metabolism / drug effects
  • Macrophages / drug effects
  • Macrophages / metabolism
  • Metabolic Syndrome / drug therapy
  • Metabolic Syndrome / genetics*
  • Organ Specificity / genetics
  • Pharmaceutical Preparations / metabolism*
  • Piperidines
  • Pyrazoles / pharmacology
  • Pyrazoles / therapeutic use
  • Pyrimidines / pharmacology
  • Pyrimidines / therapeutic use
  • Reproducibility of Results
  • Signal Transduction / genetics*
  • Zebrafish / metabolism


  • Pharmaceutical Preparations
  • Piperidines
  • Pyrazoles
  • Pyrimidines
  • ibrutinib
  • Adenine