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

Corresponding author: Jussi Pihlajamäki, .
Diabetes (Impact Factor: 8.1). 10/2012; 61(11):2807-13. DOI: 10.2337/db12-0239
Source: PubMed


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.

Download full-text


Available from: Dorota Kaminska, Jun 09, 2014
    • "Differentiation of “acute” effects of TCF7L2 manipulation and ontogenetically “chronic” effects of the transcription factor in these experiments could perhaps lift some of these controversies. Emerging data on the role of alternative splicing of the TCF7L2 transcript [42] which is regulated by metabolic factors [43] will potentially contribute to a better understanding of the gene׳s function in the future. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Deteriorating beta-cell function is a common feature of type 2 diabetes. In this review, we briefly address the regulation of beta-cell function, and discuss some of the main determinants of beta-cell failure. We will focus on the role of interactions between the genetic background and metabolic environment (insulin resistance, fuel supply and flux as well as metabolic signaling). We present data on the function of the strongest common diabetes risk variant, the single nucleotide polymorphism (SNP) rs7903146 in TCF7L2. As also mirrored by its interaction with glycemia on insulin secretion, this SNP in large part confers resistance against the incretin effect. Genetic influence on insulin secretion also interacts with free fatty acids, as evidenced by data on rs1573611 in FFAR1. Several medications marketed by now or currently under development for diabetes treatment engage these pathways, and therapeutic implications from these findings are soon to be expected.
    Molecular Metabolism 06/2014; 3(3). DOI:10.1016/j.molmet.2014.01.001
  • Source
    • "Other studies have found that the expression of TCF7L2 was decreased in human subcutaneous adipose tissue from patients with T2D, which further suggests that TCF7L2 plays a role in various metabolic tissues [104]. Furthermore, studies have shown tissue-specific alternative splicing of TCF7L2 [105–107]. However, functional studies of TCF7L2 in these other metabolic tissues are still lacking. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Elucidating the underlying genetic variations influencing various complex diseases is one of the major challenges currently facing clinical genetic research. Although these variations are often difficult to uncover, approaches such as genome-wide association studies (GWASs) have been successful at finding statistically significant associations between specific genomic loci and disease susceptibility. GWAS has been especially successful in elucidating genetic variants that influence type 2 diabetes (T2D) and obesity/body mass index (BMI). Specifically, several GWASs have confirmed that a variant in transcription factor 7-like 2 (TCF7L2) confers risk for T2D, while a variant in fat mass and obesity-associated protein (FTO) confers risk for obesity/BMI; indeed both of these signals are considered the most statistically associated loci discovered for these respective traits to date. The discovery of these two key loci in this context has been invaluable for providing novel insight into mechanisms of heritability and disease pathogenesis. As follow-up studies of TCF7L2 and FTO have typically lead the way in how to follow up a GWAS discovery, we outline what has been learned from such investigations and how they have implications for the myriad of other loci that have been subsequently reported in this disease context.
    International Journal of Endocrinology 02/2014; 2014(17):769671. DOI:10.1155/2014/769671 · 1.95 Impact Factor
  • Source
    • "Other studies demonstrated that TCF7L2 has an important role for vital functions in islet cells [8]. Recently, it has been shown that tissue-specific alternative splicing patterns of TCF7L2 mRNA variants determine insulin sensitivity of adipose tissue and are involved in the regulation of hepatic gluconeogenesis [9–11]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Polymorphisms in the transcription factor 7-like 2 (TCF7L2) gene have been shown to display a powerful association with type 2 diabetes. The aim of the present study was to evaluate metabolic alterations in carriers of a common TCF7L2 risk variant. Seventeen non-diabetic subjects carrying the T risk allele at the rs7903146 TCF7L2 locus and 24 subjects carrying no risk allele were submitted to intravenous glucose tolerance test and euglycemic-hyperinsulinemic clamp. Plasma samples were analysed for concentrations of 163 metabolites through targeted mass spectrometry. TCF7L2 risk allele carriers had a reduced first-phase insulin response and normal insulin sensitivity. Under fasting conditions, carriers of TCF7L2 rs7903146 exhibited a non-significant increase of plasma sphingomyelins (SMs), phosphatidylcholines (PCs) and lysophosphatidylcholines (lysoPCs) species. A significant genotype effect was detected in response to challenge tests in 6 SMs (C16:0, C16:1, C18:0, C18:1, C24:0, C24:1), 5 hydroxy-SMs (C14:1, C16:1, C22:1, C22:2, C24:1), 4 lysoPCs (C14:0, C16:0, C16:1, C17:0), 3 diacyl-PCs (C28:1, C36:6, C40:4) and 4 long-chain acyl-alkyl-PCs (C40:2, C40:5, C44:5, C44:6). Plasma metabolomic profiling identified alterations of phospholipid metabolism in response to challenge tests in subjects with TCF7L2 rs7903146 genotype. This may reflect a genotype-mediated link to early metabolic abnormalities prior to the development of disturbed glucose tolerance.
    PLoS ONE 10/2013; 8(10):e78430. DOI:10.1371/journal.pone.0078430 · 3.23 Impact Factor
Show more