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 6

SORLA alters levels of IR signaling in WAT in vivo.

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SORLA alters levels of IR signaling in WAT in vivo. SORLA KO, SORLA WT, ...
SORLA KO, SORLA WT, SORLA WT/Cre, and SORLA Tg mice were injected with insulin (40 μg/kg body weight), and gonadal WAT was dissected 15 minutes later. Levels of the indicated proteins in these tissues were determined by Western blotting (A and B) and by densitometric scanning of replicate blots (C–F). Protein levels in SORLA KO (A) or in SORLA Tg (B) mice were compared separately to their respective SORLA WT and SORLA WT/Cre control groups. Levels in both control lines were set to 100% and jointly referred to as CTR in C–F. The amount of SORLA positively correlates with the relative levels of p-IR (p-IR/total IR; C), p-AKT (p-AKT/total AKT; D), and PDE3β (E) in SORLA Tg as compared with SORLA CTR and SORLA KO mice. Also, SORLA levels negatively correlate with levels of cAMP-Cα (F) in these mice. n = 15–32 animals per genotype. *P < 0.05; **P < 0.01, 1-way ANOVA. The immunodetection of SORLA in A was derived from duplicate samples run on a separate gel.