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 4

SORLA levels in WAT are inversely correlated with lipolytic enzyme activities.

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SORLA levels in WAT are inversely correlated with lipolytic enzyme activ...
(A) Explants of gonadal WAT were generated from mice of the indicated genotypes and kept in culture for 72 hours. Levels of FFAs in the tissue (FFA intracellular) and the supernatant (FFA released) as well as levels of glycerol released negatively correlate with SORLA levels. n = 6–11 animals per genotype; *P < 0.05; ***P < 0.001, 1-way ANOVA. (B and C) Levels of lipase (B) and esterase activities (C) in adipocytes isolated from gonadal WAT were determined as described in Supplemental Methods and are expressed as a percentage of signal increase at OD400nm over time. Both enzyme activities are inversely correlated with SORLA levels, as seen in comparisons of SORLA KO, SORLA CTR, and SORLA Tg animals. n = 6–7 animals per genotype. P < 0.001, 2-way ANOVA. Data in A–C were determined separately in SORLA WT and SORLA WT/Cre animals. As no statistically significant difference in any parameter was noted, these 2 genotype groups were combined as the control group (CTR). P > 0.05, unpaired Student’s t test. (D and E) Levels of SORLA, total HSL and p-HSL, and cAMP-dependent protein kinase A catalytic α subunit (cAMP-Cα) (activated PKA) as well as calnexin (loading control) were determined by Western blot analysis in gonadal WAT of SORLA WT and SORLA KO animals (D) or in SORLA WT/Cre and SORLA Tg animals (E). Representative samples from 3 animals per genotype are shown. (F) Signal intensities for the indicated proteins in SORLA KO and SORLA Tg were determined by densitometric scanning of replicate blots and expressed as relative value compared with the respective control group (SORLA WT or SORLA WT/Cre) set to 100%. Both control groups are jointly referred to as CTR. A significant increase in HSL, p-HSL, and cAMP-Cα levels in SORLA KO as compared with CTR and Tg mice was noted. n = 10–12 animals per genotype. *P < 0.05; **P < 0.01; ***P < 0.001, 1-way ANOVA.