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.
View: Text | PDF
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

×

Figure 5

SORLA levels in WAT positively correlate with the extent of insulin-induced suppression of lipolysis.

Options: View larger image (or click on image) Download as PowerPoint
SORLA levels in WAT positively correlate with the extent of insulin-indu...
(A–F) Explants of gonadal WAT were generated from 4 genotype groups (SORLA KO, SORLA WT, SORLA WT/Cre, SORLA Tg) and treated in culture with the indicated substances. Thereafter, levels of FFAs in the tissues were determined. Panels B, D, F, and I display the concentration of FFAs for each genotype under untreated and treated conditions. Panels A, C, E, and H give the extent of response for each genotype expressed as percentage change compared with the respective untreated genotype control (absolute values shown in panels B, D, F, and I and set to 100% in panels A, C, E, and H). As no difference in any of the parameters was observed comparing SORLA WT and SORLA WT/Cre animals, both genotypes were combined as control (CTR) lines. (A–D) Gonadal WAT from SORLA KO, SORLA Tg, and CTR (SORLA WT and SORLA WT/Cre) mice responded to treatment (48 hours) with NE and IPT (A and B) or with forskolin and IBMX (C and D) with a comparable increase in FFA production. (E and F) Treatment with insulin for 60 minutes showed a genotype-dependent effect on FFA production with a strong reduction in SORLA Tg (51% compared with control tissue), but a lesser decrease in SORLA KO (69%) and CTR (65%) explants. n = 6–14 animal per genotype. *P < 0.05; **P < 0.01; ***P < 0.001, unpaired Student’s t test (A, C, and E); 1-way ANOVA (B, D, and F). (G) Appearance of primary adipocytes derived from preadipocytes of the indicated Sorl1 genotypes (oil red O staining). Original magnification, ×40. (H and I) Primary adipocytes of the indicated Sorl1 genotypes were treated with insulin for 30 minutes and the levels of released FFAs determined. H displays the concentration of FFAs for each genotype in the untreated and insulin-treated condition. I gives the extent of response for each genotype expressed as percentage of change compared with the respective untreated genotype control (set to 100%). Insulin-dependent suppression of FFA production is stronger in cells expressing SORLA (CTR and Tg) than in adipocytes lacking the receptor (KO). 10–12 animals per genotype. *P < 0.05; **P < 0.01; ***P < 0.001, unpaired Student’s t test (H); 1-way ANOVA (I).