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

Autor: Andersen, Emil, Ingerslev, Lars, Fabre, Odile, Donkin, Ida, Altıntaş, Ali, Versteyhe, Soetkin, Bisgaard, Thue, Kristiansen, Viggo, Simar, David, Barrès, Romain
Zdroj: International Journal of Obesity (formerly International Journal of Obesity and Related Metabolic Disorders); 20240101, Issue: Preprints p1-13, 13p
Abstrakt: 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. The transcriptomic profile of visceral adipose tissue preadipocytes collected from Lean, Obese and Obese with T2D was assessed throughout in vitrodifferentiation 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. 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 T2Dshowed 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, RBP4and CD36) were associated with DNA methylation remodelling at genes controlling insulin sensitivity and adipocytokine signalling pathways. Prior incubation of 3T3-L1 preadipocyteswith 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. 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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