Abstract
Wnt signaling is as a major regulator of adipogenesis. It differentially regulates the fate of mesenchymal stem cells (MSC) by promoting osteogenesis and myogenesis, and inhibiting adipogenesis[1]. Its loss of function has been associated with impaired osteogenesis[2] and diverse congenital and adult cardiovascular disorders[3,4]. Our group has identified loss of function mutations in Wnt coreceptor LRP6 that underlie autosomal dominant early onset coronary artery (CAD), osteoporosis and most features of the metabolic syndrome, including high plasma triglyceride and LDL-C, diabetes, hypertension, hyperuricemia and fatty liver disease (unpublished data). Following we will describe our most pertinent findings related to Wnt/LRP6 regulation of de novo lipogenesis and adipogenesis and the role of impaired Wnt signaling in generation of ectopic fat, insulin resistance, elevated plasma lipids and non-alcoholic fatty liver disease (NAFLD).
Highlights
LRP6R611C mutation carriers exhibit impaired total body insulin sensitivity compared to noncarrier relatives in response to oral glucose ingestion, which correlates with a significant decline in their skeletal muscle expression of the insulin receptor (IR)
Further investigations showed that this mutation diminishes TCF7L2-dependent transcription of the IR, whereas it increases the stability of IGFR and enhances mTORC1 pathway activity[5]
Others have shown the important role of LRP6 in increasing the expression of IR and decreasing the expression of IGF1R in preadipocytes[6]
Summary
Wnt and LRP6 regulation of insulin receptor and insulin signaling LRP6R611C mutation carriers exhibit impaired total body insulin sensitivity compared to noncarrier relatives in response to oral glucose ingestion, which correlates with a significant decline in their skeletal muscle expression of the insulin receptor (IR). Ras/Src-transformed tumors in a drosophila model of diet induced hyperglycemia and insulin resistance retained insulin sensitivity and displayed aggressive behavior toward increased metastases by increasing insulin receptor expression and preferential glucose uptake[7].
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