TCF7L2 Expression Is Regulated by Cell Differentiation and Overfeeding in Human Adipose Tissue

Abstract

ABSTRACTAim: The TCF7L2 gene variant rs7903146 has the largest effect on type 2 diabetes risk reported in genome-wide association studies, however its role in adipose tissue development and function is unknown. We investigate the association between gene variant rs7903146 and metabolic parameters and examine in vitro and ex vivo gene expression of TCF7L2 in human adipose tissue and progenitor cells from two independent populations of young healthy men with increased risk of type 2 diabetes due to low birth weight (LBW). Design: Adipose tissue biopsies were excised from 40 healthy young men with low and normal birth weights (NBW) after a control and 5-day high-fat overfeeding diet. In another cohort including 13 LBW and 13 NBW men, adipocyte progenitor cells were isolated and cultivated. Transcriptome-wide expression was performed on RNA extracted from biopsies or cell cultures. Results: Diet-induced peripheral insulin resistance is more pronounced in carriers of the T-risk allele rs7903146, whereas no association with hepatic insulin resistance was shown. TCF7L2 expression increased during adipogenesis in isolated preadipocytes from both LBW and NBW men (p < 0.001) and correlated positively with markers of progenitor cell proliferation and maturation capacity. In the mature adipose tissue, LBW men had lower expression of TCF7L2 compared to NBW men at baseline (p = 0.03) and TCF7L2 expression was suppressed by short-term overfeeding in NBW men (p = 0.005). Conclusions: The results suggest a regulation of TCF7L2 expression during adipogenesis and in mature adipose tissue upon overfeeding, and further that young men exposed to an adverse intrauterine environment have reduced mature adipose tissue TCF7L2 expression.