The Diabetes Gene and Wnt Pathway Effector TCF7L2 Regulates Adipocyte Development and Function

Abstract

The gene encoding for transcription factor 7-like 2 () is the strongest type 2 diabetes mellitus (T2DM) candidate gene discovered to date. The TCF7L2 protein is a key transcriptional effector of the Wnt/β-catenin signaling pathway, which is an important developmental pathway that negatively regulates adipogenesis. However, the precise role that TCF7L2 plays in the development and function of adipocytes remains largely unknown. Using a combination of in vitro approaches, we first show that TCF7L2 protein is increased during adipogenesis in 3T3-L1 cells and primary adipocyte stem cells and that TCF7L2 expression is required for the regulation of Wnt signaling during adipogenesis. Inactivation of TCF7L2 protein by removing the high-mobility group (HMG)-box DNA binding domain in mature adipocytes in vivo leads to whole-body glucose intolerance and hepatic insulin resistance. This phenotype is associated with increased subcutaneous adipose tissue mass, adipocyte hypertrophy, and inflammation. Finally, we demonstrate that mRNA expression is downregulated in humans with impaired glucose tolerance and adipocyte insulin resistance, highlighting the translational potential of these findings. In summary, our data indicate that TCF7L2 has key roles in adipose tissue development and function that may reveal, at least in part, how TCF7L2 contributes to the pathophysiology of T2DM.

Association of common type 1 and type 2 diabetes gene variants with latent autoimmune diabetes in adults: A meta‐analysis

“…Conversely, the recessive and TT vs CC models did not reveal a statistically significant association. A plausible mechanism by which this variant affects insulin secretion in diabetic individuals has been proposed by several studies: dysregulation of GLP‐1‐induced insulin secretion, the differential genotype‐dependent expression of insulin enhancer protein regulated by TCF7L2 for insulin secretion in human pancreatic cells and the variant affect the development of adipocytes, which may lead to insulin resistance . Furthermore, Le Bacquer et al observed increased α‐cell development and reduced β‐cell numbers primarily in larger islet cells in carriers of the TT risk genotype.…”

“…CI, confidence interval; OR, odds ratio by several studies: dysregulation of GLP-1-induced insulin secretion, the differential genotype-dependent expression of insulin enhancer protein regulated by TCF7L2 for insulin secretion in human pancreatic cells 55 and the variant affect the development of adipocytes, which may lead to insulin resistance. 56 Furthermore, Le Bacquer et al 57 observed increased α-cell development and reduced β-cell numbers primarily in larger islet cells in carriers of the TT risk genotype. Interestingly, increased TCF7L2 expression was detected in the sorted α-cells compared with β-cells of diabetic patients, 58 suggesting that this could be the reason for the increased α-/β-cell ratio in the islet cells.…”

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

“…Conversely, transgenic mice over-expressing Tcf7l2 displayed HFD-induced glucose intolerance (14). Contrasting these findings, targeted deletion of Tcf7l2 in mature adipocytes (mADs) resulted in enhanced adiposity, glucose intolerance and hyperinsulinaemia (11,12). In humans, TCF7L2 expression was decreased in the SC abdominal (hereafter referred to as abdominal) AT of subjects with impaired glucose tolerance (11) and reduced systemic insulin sensitivity (15).…”

“…Contrasting these findings, targeted deletion of Tcf7l2 in mature adipocytes (mADs) resulted in enhanced adiposity, glucose intolerance and hyperinsulinaemia (11,12). In humans, TCF7L2 expression was decreased in the SC abdominal (hereafter referred to as abdominal) AT of subjects with impaired glucose tolerance (11) and reduced systemic insulin sensitivity (15). Notably, non-coding genetic variation at the TCF7L2 locus was demonstrated to be the strongest genetic determinant of type 2 diabetes (T2D) risk in humans (16,17).…”

“…More recently, the in vitro role of TCF7L2 in the regulation of adipogenesis was revisited with conflicting results. Whilst Chen et al showed that TCF7L2 knockdown (KD) in 3T3-L1 preadipocytes leads to impaired adipocyte differentiation (11) in another study inducible TCF7L2 deletion in immortalised inguinal mouse APs was associated with enhanced adipogenesis (12). Ex vivo adipose expression of Tcf7l2 was suppressed by high-fat diet (HFD)-induced and genetic obesity (12,13).…”