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<p><b>Objective:</b> The WNT signaling pathway effector gene <i>TCF7L2</i> has been associated with an increased risk of type 2 diabetes. However, it remains unclear how this gene affects diabetic pathogenesis. The goal of this study was to investigate the effects of Tcf7l2 haploinsufficiency on metabolic phenotypes in mice.</p><p><b>Experimental Design:</b> <i>Tcf7l2</i> knockout (<i>Tcf7l</i>^-/-) mice were generated. Because of the early mortality of <i>Tcf7l2</i>^-/- mice, we characterized the metabolic phenotypes of heterozygous <i>Tcf7l2</i>^+/- mice in comparison to the wild-type controls. The mice were fed a normal chow diet or a high fat diet (HFD) for 9 weeks.</p><p><b>Results:</b> The <i>Tcf7l2</i>^+/- mice showed significant differences from the wild-type mice with regards to body weight, fasting glucose and insulin levels. <i>Tcf7l2</i>^+/- mice displayed improved glucose tolerance. In the liver of <i>Tcf7l2</i>^+/- mice fed on the HFD, reduced lipogenesis and hepatic triglyceride levels were observed when compared with those of wild-type mice. Furthermore, the <i>Tcf7l2</i>^+/- mice fed on the HFD exhibited decreased peripheral fat deposition. Immunohistochemistry in mouse pancreatic islets showed that endogenous expression of <i>Tcf7l2</i> was upregulated in the wild-type mice, but not in the <i>Tcf7l2</i>^+/- mice, after feeding with the HFD. However, the haploinsufficiency of <i>Tcf7l2</i> in mouse pancreatic islets resulted in little changes in glucose-stimulated insulin secretion.</p><p><b>Conclusion: </b>These results suggest that decreased expression of <i>Tcf7l2</i> confers reduction of diabetic susceptibility in mice <i>via</i> regulation on the metabolism of glucose and lipid.</p>