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SORLA facilitates insulin receptor signaling in adipocytes and exacerbates obesity

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Item Type:Article
Title:SORLA facilitates insulin receptor signaling in adipocytes and exacerbates obesity
Creators Name:Schmidt, V. and Schulz, N. and Yan, X. and Schuermann, A. and Kempa, S. and Kern, M. and Blueher, M. and Poy, M.N. and Olivecrona, G. and Willnow, T.E.
Abstract:In humans, genetic variation of sortilin-related receptor, L(DLR class) A repeats containing (SORL1), which encodes the intracellular sorting receptor SORLA, is a major genetic risk factor for familial and sporadic forms of Alzheimer's disease. Recent GWAS analysis has also associated SORL1 with obesity in humans and in mouse models, suggesting that this receptor may play a role in regulating metabolism. Here, using mouse models with genetic loss or tissue-specific overexpression of SORLA as well as data from obese human subjects, we observed a gene-dosage effect that links SORLA expression to obesity and glucose tolerance. Overexpression of human SORLA in murine adipose tissue blocked hydrolysis of triacylglycerides and caused excessive adiposity. In contrast, Sorl1 gene inactivation in mice accelerated breakdown of triacylglycerides in adipocytes and protected animals from diet-induced obesity. We then identified the underlying molecular mechanism whereby SORLA promotes insulin-induced suppression of lipolysis in adipocytes. Specifically, we determined that SORLA acts as a sorting factor for the insulin receptor (IR) that redirects internalized receptor molecules from endosomes to the plasma membrane, thereby enhancing IR surface expression and strengthening insulin signal reception in target cells. Our findings provide a molecular mechanism for the association of SORL1 with human obesity and confirm a genetic link between neurodegeneration and metabolism that converges on the receptor SORLA.
Keywords:Adipocytes, Adipose Tissue, Animal Disease Models, CD Antigens, Gene Dosage, Genetic Variation, Genome-Wide Association Study, Glucose, Hydrolysis, Insulin, Insulin Receptor, Knockout Mice, LDL Receptors, LDL-Receptor Related Proteins, Membrane Transport Proteins, Obesity, Risk Factors, Signal Transduction, Transgenic Mice, Triglycerides, Young Adult, Animals, Mice
Source:Journal of Clinical Investigation
ISSN:0021-9738
Publisher:American Society for Clinical Investigation (U.S.A.)
Volume:126
Number:7
Page Range:2706-2720
Date:1 July 2016
Official Publication:https://doi.org/10.1172/JCI84708
PubMed:View item in PubMed

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