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 2

Overexpression of SORLA in adipose tissue exacerbates fat tissue acquisition.

Options: View larger image (or click on image) Download as PowerPoint
Overexpression of SORLA in adipose tissue exacerbates fat tissue acquisi...
(A) Weight gain of mice of the indicated SORLA genotypes on normal chow. (B) Weight of subcutaneous WAT (sWAT) and gonadal WAT (gWAT) in mice of the indicated genotypes on normal chow. n = 6–7 per genotype. ***P < 0.001, 1-way ANOVA. No statistically significant differences in parameters shown in A and B were noted when comparing SORLA WT and SORLA WT/Cre mice (P > 0.05, unpaired Student’s t test). Thus, these 2 genotype groups were combined as the control group (CTR). (C) Gain in body weight of mice of the indicated genotypes placed on HFD at 20 week of age. n = 5–6 animals per genotype. P < 0.001 for genotype, 2-way ANOVA. (D) Lean and fat tissue mass (% of total body weight) as determined by NMR in mice fed with HFD for 15 weeks. SORLA levels positively correlate with an increase in fat and a concomitant decrease in lean tissue mass when comparing SORLA KO, SORLA CTR, and SORLA Tg animals. n = 9–10 animals per genotype. *P < 0.05, 1-way ANOVA.