Article | Published:

Preadipocytes from obese humans with type 2 diabetes are epigenetically reprogrammed at genes controlling adipose tissue function

International Journal of Obesity (2018) | Download Citation

Abstract

Background

Deterioration of the adipogenic potential of preadipocytes may contribute to adipose tissue dysfunction in obesity and type 2 diabetes (T2D). Here, we hypothesized that extracellular factors in obesity epigenetically reprogram adipogenesis potential and metabolic function of preadipocytes.

Methods

The transcriptomic profile of visceral adipose tissue preadipocytes collected from Lean, Obese and Obese with T2D was assessed throughout in vitro differentiation using RNA sequencing. Reduced Representation Bisulfite Sequencing was used to establish the genome-wide DNA methylation profile of human preadipocytes and 3T3-L1 preadipocytes treated by the inflammatory cytokine Tumour Necrosis Factor-α (TNF-α) or palmitate.

Results

While preadipocytes from all obese subjects (Obese+Obese T2D), compared to those of Lean, were transcriptionally different in response to differentiation in culture, preadipocytes from Obese T2D showed impaired insulin signalling and a further transcriptomic shift towards altered adipocyte function. Cultures with a lower expression magnitude of adipogenic genes throughout differentiation (PLIN1, CIDEC, FABP4, ADIPOQ, LPL, PDK4, APOE, LIPE, FABP3, LEP, RBP4 and CD36) were associated with DNA methylation remodelling at genes controlling insulin sensitivity and adipocytokine signalling pathways. Prior incubation of 3T3-L1 preadipocytes with TNF-α or palmitate markedly altered insulin responsiveness and metabolic function in the differentiated adipocytes, and remodelled DNA methylation and gene expression at specific genes, notably related to PPAR signalling.

Conclusions

Our findings that preadipocytes retain the memory of the donor in culture and can be reprogrammed by extracellular factors support a mechanism by which adipocyte precursors are epigenetically reprogrammed in vivo. Epigenetic reprogramming of preadipocytes represents a mechanism by which metabolic function of visceral adipose tissue may be affected in the long term by past exposure to obesity- or T2D-specific factors.

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Acknowledgements

OF was recipient of a research grant from the Danish Diabetes Academy supported by the Novo Nordisk Foundation. We would like to acknowledge The Danish National High-Throughput DNA Sequencing Centre, University of Copenhagen, for sequencing services. The Novo Nordisk Foundation Centre for Basic Metabolic Research is an independent research centre at the University of Copenhagen partially funded by an unrestricted donation from the Novo Nordisk Foundation.

Author contribution:

EA collected human samples, performed experiments, analysed the data and wrote the manuscript; LRI and AA performed bioinformatics analysis and generated figures; OF performed experiments, analysed the data and edited the manuscript; ID, SV, TB and VBK collected human samples, contributed to study design and edited the manuscript; DS provided expert advice and edited the manuscript; RB designed the study, analysed the data and wrote the manuscript. All authors approved the final version of the manuscript.

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Affiliations

  1. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

    • Emil Andersen
    • , Lars Roed Ingerslev
    • , Odile Fabre
    • , Ida Donkin
    • , Ali Altıntaş
    • , Soetkin Versteyhe
    •  & Romain Barrès
  2. Department of Surgical Gastroenterology, Hvidovre Hospital, University of Copenhagen, Copenhagen, Denmark

    • Thue Bisgaard
    •  & Viggo B. Kristiansen
  3. Mechanisms of Disease and Translational Research, School of Medical Sciences, UNSW Australia, Sydney, Australia

    • David Simar

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Conflict of interest:

The authors declare that they have no conflict of interest.

Corresponding author

Correspondence to Romain Barrès.

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DOI

https://doi.org/10.1038/s41366-018-0031-3