Abstract 140: LRP6 Influences Body Fat and Glucose Homeostasis in Mouse by Activating mTOR Pathway and Inhibiting Mitochondrial Energy Expenditure
Background: Body fat, insulin resistance and type2 diabetes are often linked together. Wnt signaling regulates adipogenesis and its altered activity has been implicated in the pathogenesis of type 2 diabetes and metabolic syndrome. Mutations in Wnt coreceptor LRP6 have been associated with diabetes, coronary heart disease and metabolic syndrome in humans, but the molecular mechanisms are largely unknown.
Methods: We study the role of LRP6 in regulation of glucose and energy metabolism in heterozygote LRP6 knockout mice on high fat diet by using glucose tolerance test, hyperinsulinemic-euglycemic clamp studies and dissection of insulin signaling pathway.
Results: LRP6+/- mice on high fat diet were protected against diet -induced obesity and hepatic and adipose tissue insulin resistance compared to wildtype littermates. Brown adipose tissue insulin sensitivity and lean body of LRP+/- mice were caused by diminished Wnt -dependent mTORC1/S6K activity and enhanced expression of brown adipose tissue PGC1-α and UCP1. LRP6+/- mice also exhibited reduced endogenous hepatic glucose output which was due to diminished FoxO1-dependent activity of G6Pase. In addition, in vivo and in vitro studies showed that loss of LRP6 allele is associated with tissue specific increase of leptin receptor expression, which is a likely cause of hepatic insulin sensitivity in LRP6+/- mice.
Conclusion: Our study identifies LRP6 as a nutrient-sensitive regulator of the body weight and glucose metabolism and as a potential target for pharmacological interventions in obesity and diabetes.
- © 2012 by American Heart Association, Inc.