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 Poy, Gunilla Olivecrona, Thomas E. Willnow

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)2706-2720
Number of pages15
JournalJournal of Clinical Investigation
Volume126
Issue number7
DOIs
StatePublished - Jul 1 2016
Externally publishedYes

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Insulin Receptor
Adipocytes
Obesity
Insulin
Gene Dosage
Lipolysis
Genome-Wide Association Study
Endosomes
Genetic Models
Adiposity
Medical Genetics
Gene Silencing
Adipose Tissue
Alzheimer Disease
Hydrolysis
Cell Membrane
Diet
Glucose

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Schmidt, V., Schulz, N., Yan, X., Schürmann, A., Kempa, S., Kern, M., ... Willnow, T. E. (2016). SORLA facilitates insulin receptor signaling in adipocytes and exacerbates obesity. Journal of Clinical Investigation, 126(7), 2706-2720. https://doi.org/10.1172/JCI84708

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

In: Journal of Clinical Investigation, Vol. 126, No. 7, 01.07.2016, p. 2706-2720.

Research output: Contribution to journalArticle

Schmidt, V, Schulz, N, Yan, X, Schürmann, A, Kempa, S, Kern, M, Blüher, M, Poy, M, Olivecrona, G & Willnow, TE 2016, 'SORLA facilitates insulin receptor signaling in adipocytes and exacerbates obesity', Journal of Clinical Investigation, vol. 126, no. 7, pp. 2706-2720. https://doi.org/10.1172/JCI84708
Schmidt V, Schulz N, Yan X, Schürmann A, Kempa S, Kern M et al. SORLA facilitates insulin receptor signaling in adipocytes and exacerbates obesity. Journal of Clinical Investigation. 2016 Jul 1;126(7):2706-2720. https://doi.org/10.1172/JCI84708
Schmidt, Vanessa ; Schulz, Nadja ; Yan, Xin ; Schürmann, Annette ; Kempa, Stefan ; Kern, Matthias ; Blüher, Matthias ; Poy, Matthew ; Olivecrona, Gunilla ; Willnow, Thomas E. / SORLA facilitates insulin receptor signaling in adipocytes and exacerbates obesity. In: Journal of Clinical Investigation. 2016 ; Vol. 126, No. 7. pp. 2706-2720.
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