PMID- 29511320
OWN - NLM
STAT- MEDLINE
DCOM- 20200103
LR  - 20220416
IS  - 1476-5497 (Electronic)
IS  - 0307-0565 (Linking)
VI  - 43
IP  - 2
DP  - 2019 Feb
TI  - Preadipocytes from obese humans with type 2 diabetes are epigenetically 
      reprogrammed at genes controlling adipose tissue function.
PG  - 306-318
LID - 10.1038/s41366-018-0031-3 [doi]
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-alpha (TNF-alpha) 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-alpha 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.
FAU - Andersen, Emil
AU  - Andersen E
AD  - Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health 
      and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
FAU - Ingerslev, Lars Roed
AU  - Ingerslev LR
AD  - Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health 
      and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
FAU - Fabre, Odile
AU  - Fabre O
AD  - Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health 
      and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
FAU - Donkin, Ida
AU  - Donkin I
AD  - Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health 
      and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
FAU - Altintas, Ali
AU  - Altintas A
AD  - Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health 
      and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
FAU - Versteyhe, Soetkin
AU  - Versteyhe S
AD  - Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health 
      and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
FAU - Bisgaard, Thue
AU  - Bisgaard T
AD  - Department of Surgical Gastroenterology, Hvidovre Hospital, University of 
      Copenhagen, Copenhagen, Denmark.
FAU - Kristiansen, Viggo B
AU  - Kristiansen VB
AD  - Department of Surgical Gastroenterology, Hvidovre Hospital, University of 
      Copenhagen, Copenhagen, Denmark.
FAU - Simar, David
AU  - Simar D
AUID- ORCID: 0000-0002-3862-1932
AD  - Mechanisms of Disease and Translational Research, School of Medical Sciences, 
      UNSW Australia, Sydney, Australia.
FAU - Barres, Romain
AU  - Barres R
AUID- ORCID: 0000-0002-0158-519X
AD  - Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health 
      and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 
      barres@sund.ku.dk.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20180220
PL  - England
TA  - Int J Obes (Lond)
JT  - International journal of obesity (2005)
JID - 101256108
SB  - IM
MH  - *Adipocytes/cytology/metabolism/physiology
MH  - *Adipose Tissue/cytology/physiology
MH  - *Diabetes Mellitus, Type 2/complications/genetics
MH  - *Epigenesis, Genetic/genetics/physiology
MH  - Gene Expression Profiling
MH  - Humans
MH  - *Obesity/complications/genetics
MH  - Transcriptome/genetics
EDAT- 2018/03/08 06:00
MHDA- 2020/01/04 06:00
CRDT- 2018/03/08 06:00
PHST- 2017/09/30 00:00 [received]
PHST- 2017/12/27 00:00 [accepted]
PHST- 2017/12/12 00:00 [revised]
PHST- 2018/03/08 06:00 [pubmed]
PHST- 2020/01/04 06:00 [medline]
PHST- 2018/03/08 06:00 [entrez]
AID - 10.1038/s41366-018-0031-3 [pii]
AID - 10.1038/s41366-018-0031-3 [doi]
PST - ppublish
SO  - Int J Obes (Lond). 2019 Feb;43(2):306-318. doi: 10.1038/s41366-018-0031-3. Epub 
      2018 Feb 20.