Targeted deletion of Tcf7l2 in adipocytes promotes adipocyte hypertrophy and impaired glucose metabolism

Abstract

Objective Activation of the Wnt-signaling pathway is known to inhibit differentiation in adipocytes. However, there is a gap in our understanding of the transcriptional network regulated by components of the Wnt-signaling pathway during adipogenesis and in adipocytes during postnatal life. The key intracellular effectors of the Wnt-signaling pathway occur through TCF transcription factors such as TCF7L2 (transcription factor-7-like 2). Several genetic variants in proximity to TCF7L2 have been linked to type 2 diabetes through genome-wide association studies in various human populations. Our work aims to functionally characterize the adipocyte specific gene program regulated by TCF7L2 and understand how this program regulates metabolism. Methods We generated Tcf7l2 F/F mice and assessed TCF7L2 function in isolated adipocytes and adipose specific knockout mice. ChIP-sequencing and RNA-sequencing was performed on the isolated adipocytes with control and TCF7L2 knockout cells. Adipose specific TCF7L2 knockout mice were challenged with high fat diet and assessed for body weight, glucose tolerance, and lipolysis. Results Here we report that TCF7L2 regulates adipocyte size, endocrine function, and glucose metabolism. Tcf7l2 is highly expressed in white adipose tissue, and its expression is suppressed in genetic and diet-induced models of obesity. Genome-wide distribution of TCF7L2 binding and gene expression analysis in adipocytes suggests that TCF7L2 directly regulates genes implicated in cellular metabolism and cell cycle control. When challenged with a high-fat diet, conditional deletion of TCF7L2 in adipocytes led to impaired glucose tolerance, impaired insulin sensitivity, promoted weight gain, and increased adipose tissue mass. This was accompanied by reduced expression of triglyceride hydrolase, reduced fasting-induced free fatty acid release, and adipocyte hypertrophy in subcutaneous adipose tissue. Conclusions Together our studies support that TCF7L2 is a central transcriptional regulator of the adipocyte metabolic program by directly regulating the expression of genes involved in lipid and glucose metabolism.

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).…”

“…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).…”

“…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). In vivo , homozygous global Tcf7l2 null mice die perinatally whereas heterozygous null animals are lean with enhanced glucose tolerance and insulin sensitivity compared to wild-type controls both on a chow and following a HFD (14).…”

Reduced expression of TCF7L2 in adipocyte impairs glucose tolerance associated with decreased insulin secretion, incretins levels and lipid metabolism dysregulation in male mice

“…Although rs7903146 in TCF7L2 is not associated with changes in overall TCF7L2 transcription (i.e. of all isoforms), with conflicting data regarding the association of rs7903146 with specific TCF7L2 variant expression in subcutaneous fat [20][21][22], TCF7L2 expression has been shown to be reduced in adipose tissue from type 2 diabetes subjects [23] and in obese mice [24]. Additionally, surgery-induced weight loss has been shown to regulate alternative splicing of Tcf7l2 in adipose tissue [25].…”

“…Efforts to understand the causal relationship between TCF7L2 and diabetes led to studies on several metabolic tissues, with the data suggesting that the combined effects of loss of TCF7L2 in multiple tissues may account for the diabetes phenotype [28]. For example, previous reports have described the impact of loss of TCF7L2 expression on adipocyte development and insulin sensitivity [24,29]. In the present study, we used a genetic model of ablation of TCF7L2 gene expression in mature adipocytes to determine whether TCF7L2 plays a role in adipocyte function, independent of its role in adipogenesis.…”