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

Emil Andersen; Lars Roed Ingerslev; Odile Fabre; Ida Donkin; Ali Altıntaş; Soetkin Versteyhe; Thue Bisgaard; Viggo B. Kristiansen; David Simar; Romain Barrès

doi:10.1038/s41366-018-0031-3

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

Emil Andersen, Lars Roed Ingerslev, Odile Fabre, Ida Donkin, Ali Altıntaş, Soetkin Versteyhe, Thue Bisgaard, Viggo B. Kristiansen, David Simar, Romain Barrès^*

^*Corresponding author for this work

Department of Clinical Medicine

12 Citations (Scopus)

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.

Original language	English
Journal	International Journal of Obesity
Volume	43
Issue number	2
Pages (from-to)	306-318
Number of pages	13
ISSN	0307-0565
DOIs	https://doi.org/10.1038/s41366-018-0031-3
Publication status	Published - 1 Feb 2019

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Andersen, E., Ingerslev, L. R., Fabre, O., Donkin, I., Altıntaş, A., Versteyhe, S., Bisgaard, T., Kristiansen, V. B., Simar, D., & Barrès, R. (2019). Preadipocytes from obese humans with type 2 diabetes are epigenetically reprogrammed at genes controlling adipose tissue function. International Journal of Obesity, 43(2), 306-318. https://doi.org/10.1038/s41366-018-0031-3

Andersen, E, Ingerslev, LR, Fabre, O, Donkin, I, Altıntaş, A, Versteyhe, S, Bisgaard, T, Kristiansen, VB, Simar, D & Barrès, R 2019, 'Preadipocytes from obese humans with type 2 diabetes are epigenetically reprogrammed at genes controlling adipose tissue function', International Journal of Obesity, vol. 43, no. 2, pp. 306-318. https://doi.org/10.1038/s41366-018-0031-3

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

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.",

author = "Emil Andersen and Ingerslev, {Lars Roed} and Odile Fabre and Ida Donkin and Ali Altınta{\c s} and Soetkin Versteyhe and Thue Bisgaard and Kristiansen, {Viggo B.} and David Simar and Romain Barr{\`e}s",

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T1 - Preadipocytes from obese humans with type 2 diabetes are epigenetically reprogrammed at genes controlling adipose tissue function

AU - Andersen, Emil

AU - Ingerslev, Lars Roed

AU - Fabre, Odile

AU - Donkin, Ida

AU - Altıntaş, Ali

AU - Versteyhe, Soetkin

AU - Bisgaard, Thue

AU - Kristiansen, Viggo B.

AU - Simar, David

AU - Barrès, Romain

PY - 2019/2/1

Y1 - 2019/2/1

N2 - 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.

AB - 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.

U2 - 10.1038/s41366-018-0031-3

DO - 10.1038/s41366-018-0031-3

M3 - Journal article

C2 - 29511320

AN - SCOPUS:85042885839

SN - 0307-0565

VL - 43

SP - 306

EP - 318

JO - International Journal of Obesity

JF - International Journal of Obesity

IS - 2

ER -

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

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