The developmental Wnt signaling pathway effector β-catenin/TCF mediates hepatic functions of the sex hormone estradiol in regulating lipid metabolism

Tian, Lili; Shao, Weijuan; Ip, Wilfred; Song, Zhuolun; Badakhshi, Yasaman; Jin, Tianru

doi:10.1371/journal.pbio.3000444

Cited by 27 publications

(30 citation statements)

References 77 publications

(125 reference statements)

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“…Thus, gender differences observed when expressing a dominant-negative form of TCF7L2 in hepatocytes would suggest that sex hormones regulate glucose homeostasis via repressing hepatic gluconeogenesis and regulate lipid metabolism [35]. In our study, we also found that female mice were largely unaffected by the loss of TCF7L2 function in the adipocyte, suggesting a role for female hormones to maintain glucose homeostasis.…”

Section: Discussionsupporting

confidence: 63%

“…Wnt and TCF7L2 are regulators of lipid metabolism in hepatocytes [35], consistent with elevated plasma triglycerides associated with TCF7L2 risk variant rs7903146 [45]. Moreover, the genetic variant is localized near the regulatory region for Acyl-CoA Synthetase Long Chain 5 (ACSL5) which activates fatty acids to generate long chain fatty acyl CoA [45].…”

Section: Discussionmentioning

confidence: 81%

“…In the present study, we found that young mice presented no alteration of glucose tolerance or body composition, regardless of the gender, in the absence of TCF7L2 in adipocyte, whilst defects appear with age ( Fig.1g and Fig.2a). Recently, Tian et al revealed crosstalk between Wnt signalling and females hormones through TCF7L2 to regulate lipid metabolism [35].…”

Section: Discussionmentioning

confidence: 99%

“…Evidence suggests a role of Wnt/TCF7L2 signalling in the control of lipid metabolism [24,35]. We, therefore, sought to determine whether TCF7L2 could play a role as a regulator of fatty acid release from mature adipocyte.…”

Section: Plasma Levels Of Incretins and Free Fatty Acids Depend On Admentioning

confidence: 99%

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

Nguyen-Tu

Martínez-Sánchez

Leclerc

et al. 2020

Preprint

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Transcription factor 7-like 2 (TCF7L2) is a downstream effector of the Wnt/beta-catenin signalling pathway and its expression is critical for adipocyte development. The precise role of TCF7L2 in glucose and lipid metabolism in adult adipocytes remains to be defined. Here, we aim to investigate how changes in TCF7L2 expression in mature adipocytes affect glucose homeostasis. Tcf7l2 was selectively ablated from mature adipocytes in C57BL/6J mice using an adiponectin promoter-driven Cre recombinase to recombine alleles floxed at exon 1 of the Tcf7l2 gene. Mice lacking Tcf7l2 in mature adipocytes displayed normal body weight. Male mice exhibited normal glucose homeostasis at eight weeks of age. Male heterozygote knockout mice (aTCF7L2het) exhibited impaired glucose tolerance (AUC increased 1.14 ± 0.04 -fold, p=0.03), as assessed by intraperitoneal glucose tolerance test, and changes in fat mass at 16 weeks (increased by 1.4 ± 0.09-fold, p=0.007). Homozygote knockout mice exhibited impaired oral glucose tolerance at 16 weeks of age (AUC increased 2.15 ± 0.15-fold, p=0.0001). Islets of Langerhans exhibited impaired glucose-stimulated insulin secretion in vitro (decreased 0.54 ± 0.13-fold aTCF7L2KO vs control, p=0.02), but no changes in in vivo glucosestimulated insulin secretion. Female mice in which one or two alleles of the Tcf7l2 gene was knocked out in adipocytes displayed no changes in glucose tolerance, insulin sensitivity or insulin secretion.Plasma levels of glucagon-like peptide-1 and gastric inhibitory polypeptide were lowered in knockout mice (decreased 0.57 ± 0.03-fold and 0.41 ± 0.12-fold, p=0.04 and p=0.002, respectively), whilst plasma free fatty acids and Fatty Acid Binding Protein 4 circulating levels were increased by 1.27 ± 0.07 and 1.78 ± 0.32-fold, respectively (p=0.05 and p=0.03). Mice with biallelic Tcf7l2 deletion exposed to high fat diet for 9 weeks exhibited impaired glucose tolerance (p=0.003 at 15 min after glucose injection) which was associated with reduced in vivo glucose-stimulated insulin secretion (decreased 0.51 ± 0.03-fold, p=0.02). Thus, our data indicate that loss of Tcf7l2 gene expression in adipocytes leads to impairments on metabolic responses which are dependent on gender, age and nutritional status. Our findings further illuminate the role of TCF7L2 in the maintenance of glucose homeostasis.

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Section: Discussionsupporting

confidence: 63%

Section: Discussionmentioning

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Section: Plasma Levels Of Incretins and Free Fatty Acids Depend On Admentioning

confidence: 99%

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

Nguyen-Tu

Martínez-Sánchez

Leclerc

et al. 2020

Preprint

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“…3), consistent with a role for female hormones in the maintenance of glucose homeostasis and differences in fat distribution between male and female mice (Figs 1, 2 and 3). Correspondingly, Tian et al [25] have previously revealed crosstalk between Wnt signalling and female hormones through TCF7L2. We therefore conducted our studies on the effects of HFD exposure (see below) in male mice only.…”

Section: Discussionmentioning

confidence: 92%

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

et al. 2020

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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.

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Hepatic Fibroblast Growth Factor 21 Is Involved in Mediating Functions of Liraglutide in Mice With Dietary Challenge

et al. 2021

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Background and Aims Several studies have shown that expression of hepatic fibroblast growth factor 21 (FGF21) can be stimulated by glucagon‐like peptide 1 (GLP‐1)–based diabetes drugs. As GLP‐1 receptor (GLP‐1R) is unlikely to be expressed in hepatocytes, we aimed to compare such stimulation in mice and in mouse hepatocytes, determine the involvement of GLP‐1R, and clarify whether FGF21 mediates certain functions of the GLP‐1R agonist liraglutide. Approach and Results Liver FGF21 expression was assessed in mice receiving a daily liraglutide injection for 3 days or in mouse primary hepatocytes (MPHs) undergoing direct liraglutide treatment. The effects of liraglutide on metabolic improvement and FGF21 expression were then assessed in high‐fat diet (HFD)‐fed mice and compared with the effects of the dipeptidyl‐peptidase 4 inhibitor sitagliptin. Animal studies were also performed in Glp1r−/− mice and liver‐specific FGF21‐knockout (lFgf21‐KO) mice. In wild‐type mouse liver that underwent RNA sequencing and quantitative reverse‐transcription PCR, we observed liraglutide‐stimulated hepatic Fgf21 expression and a lack of Glp1r expression. In MPHs, liraglutide did not stimulate Fgf21. In mice with HFD‐induced obesity, liraglutide or sitagliptin treatment reduced plasma triglyceride levels, whereas their effect on reducing body‐weight gain was different. Importantly, increased hepatic FGF21 expression was observed in liraglutide‐treated mice but was not observed in sitagliptin‐treated mice. In HFD‐fed Glp1r−/− mice, liraglutide showed no beneficial effects and could not stimulate Fgf21 expression. In lFgf21‐KO mice undergoing dietary challenge, the body‐weight‐gain attenuation and lipid homeostatic effects of liraglutide were lost or significantly reduced. Conclusions We suggest that liraglutide‐stimulated hepatic Fgf21 expression may require GLP‐1R to be expressed in extrahepatic organs. Importantly, we revealed that hepatic FGF21 is required for liraglutide to lower body weight and improve hepatic lipid homeostasis. These observations advanced our mechanistic understanding of the function of GLP‐1–based drugs in NAFLD.

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The developmental Wnt signaling pathway effector β-catenin/TCF mediates hepatic functions of the sex hormone estradiol in regulating lipid metabolism

Cited by 27 publications

References 77 publications

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

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

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

Hepatic Fibroblast Growth Factor 21 Is Involved in Mediating Functions of Liraglutide in Mice With Dietary Challenge

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