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 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 11

SORLA promotes recycling of internalized IR to the cell surface in primary adipocytes.

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SORLA promotes recycling of internalized IR to the cell surface in prima...
(A) Replicate layers of primary adipocytes from SORLA KO and SORLA Tg mice were blocked at 4°C and cell surface–exposed IR molecules tagged with anti-IR IgG. Subsequently, 10 μg/ml insulin was added to the medium and cells shifted to 37°C. At time points 5 and 30 minutes, the cells were costained for the tagged IR molecules (red) and markers RAB11 or RAB9 (green). In SORLA KO adipocytes, the IR colocalizes preferentially with RAB9 (see merged images in the insets). In contrast, in SORLA Tg adipocytes, the IR colocalizes with RAB11 after 30 minutes of chase. Both overview and inset images were acquired at ×60 magnification. Overview images were shrunk to 30% of original size. (B and C) Experiments as exemplified in A were performed and the colocalization of the IR with RAB11 (B) and RAB9 (C) evaluated by Pearson’s correlation coefficient (r). The IR preferentially colocalized with RAB11 in SORLA Tg, but with RAB9 in SORLA KO adipocytes. n = 20–30 cells per genotype. *P < 0.05; ***P < 0.001, 2-way ANOVA.