Adipocyte-specific deletion of Tcf7l2 induces dysregulated lipid metabolism and impairs glucose tolerance in mice

Abstract

Aims/hypothesis Transcription factor 7-like 2 (TCF7L2) is a downstream effector of the Wnt/β-catenin signalling pathway implicated in type 2 diabetes risk through genome-wide association studies. Although its expression is critical for adipocyte development, the potential roles of changes in adipose tissue TCF7L2 levels in diabetes risk are poorly defined. Here, we investigated whether forced changes in Tcf7l2 expression in adipocytes affect whole body glucose or lipid metabolism and crosstalk between disease-relevant tissues. Methods Tcf7l2 was selectively ablated in mature adipocytes in C57BL/6J mice using Cre recombinase under Adipoq promoter control to recombine Tcf7l2 alleles floxed at exon 1 (referred to as aTCF7L2 mice). aTCF7L2 mice were fed normal chow or a high-fat diet for 12 weeks. Glucose and insulin sensitivity, as well as beta cell function, were assessed in vivo and in vitro. Levels of circulating NEFA, selected hormones and adipokines were measured using standard assays. Results Reduced TCF7L2 expression in adipocytes altered glucose tolerance and insulin secretion in male but not in female mice. Thus, on a normal chow diet, male heterozygote knockout mice (aTCF7L2het) exhibited impaired glucose tolerance at 16 weeks (p = 0.03) and increased fat mass (1.4 ± 0.1-fold, p = 0.007) but no changes in insulin secretion. In contrast, male homozygote knockout (aTCF7L2hom) mice displayed normal body weight but impaired oral glucose tolerance at 16 weeks (p = 0.0001). These changes were mechanistically associated with impaired in vitro glucose-stimulated insulin secretion (decreased 0.5 ± 0.1-fold vs control mice, p = 0.02) and decreased levels of the incretins glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (0.6 ± 0.1-fold and 0.4 ± 0.1-fold vs control mice, p = 0.04 and p < 0.0001, respectively). Circulating levels of plasma NEFA and fatty acid binding protein 4 were increased by 1.3 ± 0.1-fold and 1.8 ± 0.3-fold vs control mice (p = 0.03 and p = 0.05, respectively). Following exposure to a high-fat diet for 12 weeks, male aTCF7L2hom mice exhibited reduced in vivo glucose-stimulated insulin secretion (0.5 ± 0.1-fold vs control mice, p = 0.02). Conclusions/interpretation Loss of Tcf7l2 gene expression selectively in adipocytes leads to a sexually dimorphic phenotype, with impairments not only in adipocytes, but also in pancreatic islet and enteroendocrine cells in male mice only. Our findings suggest novel roles for adipokines and incretins in the effects of diabetes-associated variants in TCF7L2, and further illuminate the roles of TCF7L2 in glucose homeostasis and diabetes risk.

Wnt Signaling: From Mesenchymal Cell Fate to Lipogenesis and Other Mature Adipocyte Functions

“…However, increasing genetic evidence in humans has linked various Wnt pathway members to body fat distribution, obesity, and metabolic dysfunction. In recent years, a flurry of global and adipose-targeted studies in mice has provided compelling, albeit in some cases contradictory, evidence that Wnt signaling plays important roles in accumulation of adipose tissues and in whole-body glucose and lipid metabolism, particularly under obesogenic conditions (53)(54)(55)59,(61)(62)(63). Indeed, adipocyte-specific deletion of various Wnt pathway members, including Ctnnb1, Wls, and Tcf7l2, has been shown to influence lipogenic gene expression, underscoring the critical importance of Wnt signaling in adipocyte lipogenesis.…”

Metabolic Contributions of Wnt Signaling: More Than Controlling Flight

“…Further studies done by Nguyen-Tu et al (2021) on TCF7L2 knockout mice using an Adipoq-Cre driver recapitulated the hyperglycemic phenotype seen by Chen et al (2018). However, this phenotype was only seen in 16-week old males, and they were not insulin resistant.…”

“…The Tcf7l2 gene contains 17 exons, as denoted by numerated blue rectangles. Recombination of floxed alleles for Exon 1 ( Nguyen-Tu et al, 2021 ), Exon 5 ( Geoghegan et al, 2019 ), and Exon 11 (Chen et al) by Cre recombinase under the control of the Adipoq promoter results in different metabolic phenotypes. This figure was made with modified images from Servier Medical Art (Creative Commons Attribution 3.0 Unported License).…”

“…No differences in insulin secretion were seen in vivo under normal chow-fed conditions, possibly due to compensatory increases in circulating levels of NEFAs that can potentiate glucose-stimulated insulin secretion. Furthermore, under high-fat diet, no weight changes were seen but TCFL2 knockout diminished insulin secretion ( Nguyen-Tu et al, 2021 ).…”

“…Chen et al, floxed exon 11, known to encode the DNA binding HMG box ( Hansson et al, 2010 ). On the other hand, Geoghegan et al (2019) used mice with lox-p sites flanking exon 5, while Nguyen-Tu et al (2021) used exon 1 floxed mice. Both found TCF7L2 to have an inhibitory role on adipogenesis.…”