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.


METHODS
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.


CONCLUSIONS
These results suggest that decreased expression of Tcf7l2 confers reduction of diabetic susceptibility in mice via regulation on the metabolism of glucose and lipid.
Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201, USA.
Hyekyung
H
Yang
Qing
Q
Li
Jong-Hwan
JH
Lee
Yan
Y
Shu
D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003920:Diabetes Mellitus / Q000139:chemically induced / Q000378:metabolism* / Q000517:prevention & control; D059305:Diet, High-Fat / Q000009:adverse effects*; D007515:Islets of Langerhans / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058118:Transcription Factor 7-Like 2 Protein / Q000235:genetics / Q000378:metabolism*
D001786:Blood Glucose; D058118:Transcription Factor 7-Like 2 Protein