SORLA facilitates insulin receptor signaling in adipocytes and exacerbates obesity
Vanessa Schmidt, Nadja Schulz, Xin Yan, Annette Schürmann, Stefan Kempa, Matthias Kern, Matthias Blüher, Matthew N. Poy, Gunilla Olivecrona, Thomas E. Willnow
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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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 9

SORLA interacts with the IR to increase cell surface exposure.

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SORLA interacts with the IR to increase cell surface exposure. (A) Paren...
(A) Parental CHO cells and CHO-S cells were subjected to immunoprecipitation using anti-SORLA antiserum. Input represents Western blot analyses of cell lysates prior to immunoprecipitation. IP depicts SORLA and IR in the precipitate. Precipitation of SORLA from CHO-S (lane 1) results in coimmunoprecipitation of the IR. No (co)immunoprecipitation of SORLA and IR is seen in parental CHO cells lacking SORLA (lane 2) or in CHO-S cells without addition of anti-SORLA IgG (w/o IgG; lane 3). (B and C) Replicate layers of CHO and CHO-S cells were treated with sulfo-NHS-S-S-biotin and biotinylated surface proteins precipitated by streptavidin beads. The amount of IR in total cell lysates (total levels) and in the biotinylated fraction (surface) was determined by Western blotting (B). Cell surface levels of the IR are increased in CHO-S as compared with parental CHO cells (relative levels set to 100%), as shown by densitometric scanning of replicate experiments (C). n = 10. ***P < 0.001, unpaired Student’s t test. (D) Coimmunoprecipitation of endogenous IR with endogenous SORLA from gonadal WAT of SORLA WT but not SORLA KO mice using anti-SORLA IgG (IP SORLA). Input documents levels of SORLA and IR in SORLA WT and SORLA KO WAT prior to immunoprecipitation. (E and F) MEFs from SORLA WT and SORLA KO mice were differentiated to adipocytes. Replicate layers of adipocytes were treated with sulfo-NHS-S-S-biotin and biotinylated surface proteins precipitated by streptavidin beads. The amount of IR in total cell lysates (total) and in the biotinylated fraction (surface) was determined by Western blotting (E) and by densitometric scanning of replicate experiments (F). The total levels of the IR are unchanged, but the cell surface levels decreased in SORLA KO as compared with SORLA WT adipocytes (relative levels set to 100%). n = 6–7 per genotype. *P < 0.05, unpaired Student’s t test.