Adipose Tissue TCF7L2 Splicing Is Regulated by Weight Loss and Associates With Glucose and Fatty Acid Metabolism

Abstract

We investigated the effects of obesity surgery-induced weight loss on transcription factor 7-like 2 gene (TCF7L2) alternative splicing in adipose tissue and liver. Furthermore, we determined the association of TCF7L2 splicing with the levels of plasma glucose and serum free fatty acids (FFAs) in three independent studies (n = 216). Expression of the short mRNA variant, lacking exons 12, 13, and 13a, decreased after weight loss in subcutaneous fat (n = 46) and liver (n = 11) and was more common in subcutaneous fat of subjects with type 2 diabetes than in subjects with normal glucose tolerance in obese individuals (n = 54) and a population-based sample (n = 49). Additionally, there was a positive correlation between this variant and the level of fasting glucose in nondiabetic individuals (n = 113). This association between TCF7L2 splicing and plasma glucose was independent of the TCF7L2 genotype. Finally, this variant was associated with high levels of serum FFAs during hyperinsulinemia, suggesting impaired insulin action in adipose tissue, whereas no association with insulin secretion or insulin-stimulated whole-body glucose uptake was observed. Our study shows that the short TCF7L2 mRNA variant in subcutaneous fat is regulated by weight loss and is associated with hyperglycemia and impaired insulin action in adipose tissue.

Adipose tissue INSR splicing in humans associates with fasting insulin level and is regulated by weight loss

“…In addition, we have shown that the splicing of TCF7L2 is regulated by weight loss in adipose tissue and liver [4]. Thus, we hypothesised that adipose tissue INSR splicing is modified by weight loss through changes in splicing factor gene expression levels.…”

“…In addition, subcutaneous fat biopsies were taken 1 year after the surgery. Visceral biopsies (n =81) were collected at the baseline [4]. Two independent study groups were used for the replication of the results.…”

“…Subcutaneous tissue biopsies were collected at all visits (baseline, 7 weeks and 24 weeks). Second, subcutaneous adipose tissue samples from a total of 49 men (21 with type 2 diabetes, 28 with normal glucose tolerance) were included from the population-based METSIM study [4] (Table 1). Diabetic status was determined using the ADA 2003 criteria.…”

“…Thus, we hypothesised that adipose tissue INSR splicing is modified by weight loss through changes in splicing factor gene expression levels. To test this hypothesis we determined the association of INSR splicing with metabolic variables and the expression of splicing factors in three independent studies (n =189 combined): Kuopio Obesity Surgery study (KOBS, n =108) [4], a very low calorie diet (VLCD) intervention (n = 32) [5] and the population-based Metabolic Syndrome in Men study (METSIM, n =49) [4].…”

Characterization of the transcriptional machinery bound across the widely presumed type 2 diabetes causal variant, rs7903146, within TCF7L2

“…It was initially speculated that TCF7L2 operated in tandem with insulin to influence blood glucose homeostasis through the alteration of levels of glucagon-like peptide 1 in the gut, 6,10 with knockout mouse models suggesting that TCF7L2 has an indispensable role in intestinal epithelium development. 11 However, other studies have shown that the TCF7L2 variant is associated with increased TCF7L2 expression and decreased insulin secretion, possibly implicating the pancreatic b-cell, 12,13 although an indirect effect on insulin secretion by TCF7L2 action in another tissue cannot be excluded, including adipose 14 and liver. 15 Resolving the underlying functional mechanism to a given genetic association in the post-GWAS era has proven extremely challenging.…”