Reduction in Tcf7l2 Expression Decreases Diabetic Susceptibility in Mice

Objective: The WNT signaling pathway effector gene TCF7L2 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. Experimental Design: Tcf7l2 knockout (Tcf7l-/-) mice were generated. Because of the early mortality of Tcf7l2-/- mice, we characterized the metabolic phenotypes of heterozygous Tcf7l2+/- 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. Results: The Tcf7l2+/- mice showed significant differences from the wild-type mice with regards to body weight, fasting glucose and insulin levels. Tcf7l2+/- mice displayed improved glucose tolerance. In the liver of Tcf7l2+/- mice fed on the HFD, reduced lipogenesis and hepatic triglyceride levels were observed when compared with those of wild-type mice. Furthermore, the Tcf7l2+/- mice fed on the HFD exhibited decreased peripheral fat deposition. Immunohistochemistry in mouse pancreatic islets showed that endogenous expression of Tcf7l2 was upregulated in the wild-type mice, but not in the Tcf7l2+/- mice, after feeding with the HFD. However, the haploinsufficiency of Tcf7l2 in mouse pancreatic islets resulted in little changes in glucose-stimulated insulin secretion. Conclusion: These results suggest that decreased expression of Tcf7l2 confers reduction of diabetic susceptibility in mice via regulation on the metabolism of glucose and lipid.