Network-based integration of molecular and physiological data elucidates regulatory mechanisms underlying adaptation to high-fat diet

Davina Derous, Thomas Kelder, Evert M van Schothorst, Marjan van Erk, Anja Voigt, Susanne Klaus, Jaap Keijer, Marijana Radonjic

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Abstract

Health is influenced by interplay of molecular, physiological and environmental factors. To effectively maintain health and prevent disease, health-relevant relations need to be understood at multiple levels of biological complexity. Network-based methods provide a powerful platform for integration and mining of data and knowledge characterizing different aspects of health. Previously, we have reported physiological and gene expression changes associated with adaptation of murine epididymal white adipose tissue (eWAT) to 5 days and 12 weeks of high-fat diet (HFD) and low-fat diet feeding (Voigt et al. in Mol Nutr Food Res 57:1423-1434, 2013. doi: 10.1002/mnfr.201200671 ). In the current study, we apply network analysis on this dataset to comprehensively characterize mechanisms driving the short- and long-term adaptation of eWAT to HFD across multiple levels of complexity. We built a three-layered interaction network comprising enriched biological processes, their transcriptional regulators and associated changes in physiological parameters. The multi-layered network model reveals that early eWAT adaptation to HFD feeding involves major changes at a molecular level, including activation of TGF-β signalling pathway, immune and stress response and downregulation of mitochondrial functioning. Upon prolonged HFD intake, initial transcriptional response tails off, mitochondrial functioning is even further diminished, and in turn the relation between eWAT gene expression and physiological changes becomes more prominent. In particular, eWAT weight and total energy intake negatively correlate with cellular respiration process, revealing mitochondrial dysfunction as a hallmark of late eWAT adaptation to HFD. Apart from global understanding of the time-resolved adaptation to HFD, the multi-layered network model allows several novel mechanistic hypotheses to emerge: (1) early activation of TGF-β signalling as a trigger for structural and morphological changes in mitochondrial organization in eWAT, (2) modulation of cellular respiration as an intervention strategy to effectively deal with excess dietary fat and (3) discovery of putative intervention targets, such those in pathways related to appetite control. In conclusion, the generated network model comprehensively characterizes eWAT adaptation to high-fat diet, spanning from global aspects to mechanistic details. Being open to further exploration by the research community, it provides a resource of health-relevant interactions ready to be used in a broad range of research applications.

Original languageEnglish
Article number22
Number of pages11
JournalGenes & Nutrition
Volume10
Issue number4
Early online date28 May 2015
DOIs
Publication statusPublished - 2015

Fingerprint

White Adipose Tissue
High Fat Diet
Cell Respiration
Health
Biological Phenomena
Gene Expression
Fat-Restricted Diet
Data Mining
Health Resources
Dietary Fats
Appetite
Energy Intake
Research
Down-Regulation
Organizations
Weights and Measures
Food

Keywords

  • network analysis
  • systems biology
  • adipose tissues
  • high-fat diet
  • data integration
  • transcriptional regulation
  • transcriptomics

Cite this

Network-based integration of molecular and physiological data elucidates regulatory mechanisms underlying adaptation to high-fat diet. / Derous, Davina; Kelder, Thomas; van Schothorst, Evert M; van Erk, Marjan; Voigt, Anja; Klaus, Susanne; Keijer, Jaap; Radonjic, Marijana.

In: Genes & Nutrition, Vol. 10, No. 4, 22, 2015.

Research output: Contribution to journalArticle

Derous, Davina ; Kelder, Thomas ; van Schothorst, Evert M ; van Erk, Marjan ; Voigt, Anja ; Klaus, Susanne ; Keijer, Jaap ; Radonjic, Marijana. / Network-based integration of molecular and physiological data elucidates regulatory mechanisms underlying adaptation to high-fat diet. In: Genes & Nutrition. 2015 ; Vol. 10, No. 4.
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note = "Acknowledgments We thank members of BIOCLAIMS consortium and of TNO department Microbiology and Systems Biology for their useful feedback during execution of this project. The research leading to these results has received funding from the European Union’s Seventh Framework Programme FP7 2007–2013 under Grant Agreement No 244995 (BIOCLAIMS Project).",
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AU - Keijer, Jaap

AU - Radonjic, Marijana

N1 - Acknowledgments We thank members of BIOCLAIMS consortium and of TNO department Microbiology and Systems Biology for their useful feedback during execution of this project. The research leading to these results has received funding from the European Union’s Seventh Framework Programme FP7 2007–2013 under Grant Agreement No 244995 (BIOCLAIMS Project).

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