TCF7L2 plays a complex role in human adipose progenitor biology which may contribute to genetic susceptibility to type 2 diabetes

<jats:title>ABSTRACT</jats:title><jats:p>Non-coding genetic variation at <jats:italic>TCF7L2</jats:italic> is the strongest genetic determinant of type 2 diabetes (T2D) risk in humans. TCF7L2 encodes a transcription factor mediating the nuclear effects of WNT signalling in adipose tissue (AT). Here we mapped the expression of <jats:italic>TCF7L2</jats:italic> in human AT and investigated its role in adipose progenitor (AP) biology. APs exhibited the highest <jats:italic>TCF7L2</jats:italic> mRNA abundance compared to mature adipocytes and adipose-derived endothelial cells. Obesity was associated with reduced <jats:italic>TCF7L2</jats:italic> transcript levels in subcutaneous abdominal AT but increased expression in APs. In functional studies, TCF7L2 knockdown (KD) in APs led to dose-dependent activation of WNT/β-catenin signaling, impaired proliferation and dose-dependent effects on adipogenesis. Whilst partial KD enhanced adipocyte differentiation, complete KD impaired lipid accumulation and adipogenic gene expression. Overexpression of TCF7L2 accelerated adipogenesis. Transcriptome-wide profiling revealed that TCF7L2 can modulate multiple aspects of AP biology including extracellular matrix secretion, immune signalling and apoptosis. The T2D-risk allele at rs7903146 was associated with reduced AP <jats:italic>TCF7L2</jats:italic> expression and enhanced AT insulin sensitivity. Our study highlights a complex role for TCF7L2 in AP biology and suggests that in addition to regulating pancreatic insulin secretion, genetic variation at <jats:italic>TCF7L2</jats:italic> may also influence T2D risk by modulating AP function.</jats:p>