Diabetologia. 2016 Dec;59(12):2664-2673.

Epigenetic programming of adipose-derived stem cells in low birthweight individuals.

Broholm C1, Olsson AH2, Perfilyev A3, Hansen NS2,4, Schrölkamp M2, Strasko KS2, Scheele C4,5, Ribel-Madsen R2,6, Mortensen B7, Jørgensen SW7, Ling C3, Vaag A2,4,7.

Author information

1Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet – Section 7652, Tagensvej 20, DK-2200, Copenhagen, Denmark. christa.broholm@gmail.com.
2Department of Endocrinology, Diabetes and Metabolism, Rigshospitalet – Section 7652, Tagensvej 20, DK-2200, Copenhagen, Denmark.
3Department of Clinical Sciences, Epigenetics and Diabetes, Lund University Diabetes Centre, CRC, Malmö, Sweden.
4Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
5Centre of Inflammation and Metabolism, Rigshospitalet, Copenhagen, Denmark.
6Danish Diabetes Academy, Odense, Denmark.
7Steno Diabetes Center A/S, Gentofte, Denmark.

 

Abstract

AIMS/HYPOTHESIS:

Low birthweight (LBW) is associated with dysfunctions of adipose tissue and metabolic disease in adult life. We hypothesised that altered epigenetic and transcriptional regulation of adipose-derived stem cells (ADSCs) could play a role in programming adipose tissue dysfunction in LBW individuals.

METHODS:

ADSCs were isolated from the subcutaneous adipose tissue of 13 normal birthweight (NBW) and 13 LBW adult men. The adipocytes were cultured in vitro, and genome-wide differences in RNA expression and DNA methylation profiles were analysed in ADSCs and differentiated adipocytes.

RESULTS:

We demonstrated that ADSCs from LBW individuals exhibit multiple expression changes as well as genome-wide alterations in methylation pattern. Reduced expression of the transcription factor cyclin T2 encoded by CCNT2 may play a key role in orchestrating several of the gene expression changes in ADSCs from LBW individuals. Indeed, silencing of CCNT2 in human adipocytes decreased leptin secretion as well as the mRNA expression of several genes involved in adipogenesis, including MGLL, LIPE, PPARG, LEP and ADIPOQ. Only subtle genome-wide mRNA expression and DNA methylation changes were seen in mature cultured adipocytes from LBW individuals.

CONCLUSIONS/INTERPRETATION:

Epigenetic and transcriptional changes in LBW individuals are most pronounced in immature ADSCs that in turn may programme physiological characteristics of the mature adipocytes that influence the risk of metabolic diseases. Reduced expression of CCNT2 may play a key role in the developmental programming of adipose tissue.

KEYWORDS:

Adipocytes; Adipogenesis; Adipose tissue; Cyclin T2; Epigenetics; Fetal programming; Low birthweight; Metabolic disease; Type 2 diabetes

PMID: 27627980

 

Being an offspring of a mother with gestational diabetes (O-GDM) or type 1 diabetes (=-T1D) is associated with an increased risk of developing obesity, metabolic syndrome and type 2 diabetes (T2D) in adulthood. The concept of epigenetics has for some time been considered to explain how adverse events in fetal life may confer increased disease susceptibility. However, studies of offspring of mothers with diabetes in pregnancy have so far have not provided solid evidence to explain the mechanisms underlying the strong association between fetal hyperglycemia and development of T2D in adult life.

We show that preadipocytes isolated from male O-GDM (n=18) and O-T1D (n=18) are enlarged in vivo and display functional defects when cultured in vitro including decreased maximal mitochondrial capacity and increased lipolysis when supplemented with fatty-acids compared to adipocytes established from male offspring from the background population (O-BP) (n=16). These functional defects are associated with a decreased methylation in the LEP promoter and an increased leptin expression and secretion. Taken together, these findings show that epigenetic and functional changes exist in preadipocyte cultures from individuals exposed to fetal hyperglycemia who are at increased risk of developing metabolic disease.

All together, we sincerely believe that our results provide important new insights into how adverse events occurring in fetal life can induce persistent functional changes in preadipocytes, potentially explaining important aspects of the association between the increased disease risks in offspring of mothers with diabetes in pregnancy.