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 glucose-stimulated 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.

中文翻译：

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TCF7L2在脂肪细胞中的表达降低会损害与雄性小鼠胰岛素分泌减少，肠降血糖素水平和脂质代谢失调有关的葡萄糖耐量

转录因子7样2（TCF7L2）是Wnt /β-catenin信号通路的下游效应子，其表达对于脂肪细胞的发育至关重要。TCF7L2在成年脂肪细胞中葡萄糖和脂质代谢中的确切作用尚待确定。在这里，我们旨在研究成熟脂肪细胞中TCF7L2表达的变化如何影响葡萄糖稳态。使用脂联素启动子驱动的Cre重组酶从C57BL / 6J小鼠的成熟脂肪细胞中选择性切除Tcf7l2，以重组在Tcf7l2基因外显子1上浮游的等位基因。在成熟脂肪细胞中缺乏Tcf7l2的小鼠体重正常。雄性小鼠在八周龄时表现出正常的葡萄糖稳态。雄性杂合子敲除小鼠（aTCF7L2het）糖耐量受损（AUC增加1.14±0.04-倍，p = 0.03），如通过腹膜内葡萄糖耐量试验评估的，以及16周时脂肪量的变化（增加1.4±0.09倍，p = 0.007）。纯合子敲除小鼠在16周龄时表现出受损的口服葡萄糖耐量（AUC增加2.15±0.15倍，p = 0.0001）。Langerhans胰岛在体外表现出葡萄糖刺激的胰岛素分泌受损（相对于对照，aTCF7L2KO降低了0.54±0.13倍，p = 0.02），但体内葡萄糖刺激的胰岛素分泌没有变化。Tcf7l2基因的一个或两个等位基因在脂肪细胞中被剔除的雌性小鼠在葡萄糖耐量，胰岛素敏感性或胰岛素分泌方面没有变化。敲除小鼠的血浆胰高血糖素样肽1和胃抑制性多肽水平降低（分别降低了0.57±0.03倍和0.41±0.12倍，p = 0.04和p = 0.002），而血浆游离脂肪酸和脂肪酸结合蛋白4的循环水平分别提高了1.27±0.07和1.78±0.32倍（p = 0.05和p = 0.03）。暴露于高脂饮食9周的双等位基因Tcf7l2缺失的小鼠表现出葡萄糖耐量降低（葡萄糖注射后15分钟，p = 0.003），这与体内葡萄糖刺激的胰岛素分泌减少（0.51±0.03倍降低，p = 0.02）。因此，我们的数据表明，脂肪细胞中Tcf7l2基因表达的缺失导致代谢反应受到损害，这取决于性别，年龄和营养状况。我们的发现进一步阐明了TCF7L2在维持葡萄糖稳态中的作用。暴露于高脂饮食9周的双等位基因Tcf7l2缺失的小鼠表现出葡萄糖耐量降低（葡萄糖注射后15分钟，p = 0.003），这与体内葡萄糖刺激的胰岛素分泌减少（0.51±0.03倍降低，p = 0.02）。因此，我们的数据表明，脂肪细胞中Tcf7l2基因表达的缺失导致代谢反应受到损害，这取决于性别，年龄和营养状况。我们的发现进一步阐明了TCF7L2在维持葡萄糖稳态中的作用。暴露于高脂饮食9周的双等位基因Tcf7l2缺失的小鼠表现出葡萄糖耐量降低（葡萄糖注射后15分钟，p = 0.003），这与体内葡萄糖刺激的胰岛素分泌减少（0.51±0.03倍降低，p = 0.02）。因此，我们的数据表明，脂肪细胞中Tcf7l2基因表达的缺失导致代谢反应受到损害，这取决于性别，年龄和营养状况。我们的发现进一步阐明了TCF7L2在维持葡萄糖稳态中的作用。我们的数据表明，脂肪细胞中Tcf7l2基因表达的缺失会导致代谢反应受损，这取决于性别，年龄和营养状况。我们的发现进一步阐明了TCF7L2在维持葡萄糖稳态中的作用。我们的数据表明，脂肪细胞中Tcf7l2基因表达的缺失会导致代谢反应受损，这取决于性别，年龄和营养状况。我们的发现进一步阐明了TCF7L2在维持葡萄糖稳态中的作用。