SORLA facilitates insulin receptor signaling in adipocytes and exacerbates obesity
Vanessa Schmidt, … , Gunilla Olivecrona, Thomas E. Willnow
Vanessa Schmidt, … , Gunilla Olivecrona, Thomas E. Willnow
Published July 1, 2016; First published June 20, 2016
Citation Information: J Clin Invest. 2016;126(7):2706-2720. https://doi.org/10.1172/JCI84708.
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Research Article Metabolism

SORLA facilitates insulin receptor signaling in adipocytes and exacerbates obesity

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.

Authors

Vanessa Schmidt, Nadja Schulz, Xin Yan, Annette Schürmann, Stefan Kempa, Matthias Kern, Matthias Blüher, Matthew N. Poy, Gunilla Olivecrona, Thomas E. Willnow

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Figure 1

Loss of SORLA protects from diet-induced obesity.

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Loss of SORLA protects from diet-induced obesity. (A) Gain of body weigh...
(A) Gain of body weight of SORLA WT and SORLA KO mice placed on a HFD at 35 weeks of age (n = 11–12 animals per genotype; 2-way ANOVA; P = 0.02 for genotypes). (B) Weight gain of SORLA WT and SORLA KO mice on normal chow. (C) Lean and fat tissue mass (% of total body weight) in SORLA WT and SORLA KO mice on normal chow as determined by NMR at 5 and 12 months of age. SORLA KO mice show an increase in lean and a concomitant decrease in fat tissue mass compared with SORLA WT animals. n = 5–6 animals per genotype. *P < 0.05; **P < 0.01, unpaired Student’s t test.