The developmental and metabolic roles of the diabetes candidate gene TCF7L2 in adipose tissue

The gene encoding for transcription factor 7-like 2 (TCF7L2) is the strongest type 2 diabetes (T2DM) candidate gene discovered to date. While its association with T2DM has been replicated in most populations worldwide, the molecular and physiological mechanisms that underlie this association remain largely unknown. As a key transcriptional effector of the Wnt/β-catenin signaling pathway, we hypothesized that TCF7L2 plays an important role in the development and function of adipocytes. Using a combination of in vitro and in vivo approaches, we show that TCF7L2 is critical for proper adipogenesis and that inactivating TCF7L2 mediated transcription by removing its DNA binding domain in mature adipocytes leads to whole-body glucose intolerance and hepatic insulin resistance in mice. This effect is secondary to an increase in subcutaneous adipose tissue mass caused by adipocyte hypertrophy that worsens with age and with high-fat feeding. Finally, in humans with adipocyte insulin resistance we demonstrate that TCF7L2 expression is downregulated, highlighting the translational importance of our findings. In summary our data indicate that TCF7L2 is an important mediator of adipocyte biology and has key roles in adipose tissue development and function. For the identification of genes regulated during adipogenesis by Tcf7l2, Tcf7l2 was silenced in murine 3T3-L1 preadipocyte cells using lentivirally delivered stable silencing of Tcf7l2 with a scrambled shRNA as control. Sampling times were at 0, 2, 4, 6, and 8 days of differentiation. RNA-seq timecourse was performed in duplicate.