SORLA facilitates insulin receptor signaling in adipocytes and exacerbates obesity.
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.
Vanessa
V
Schmidt
Nadja
N
Schulz
Xin
X
Yan
Annette
A
Schürmann
Stefan
S
Kempa
Matthias
M
Kern
Matthias
M
Blüher
Matthew N
MN
Poy
Gunilla
G
Olivecrona
Thomas E
TE
Willnow
D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D018628:Gene Dosage; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D005947:Glucose / Q000737:chemistry; D006801:Humans; D006868:Hydrolysis; D007328:Insulin / Q000378:metabolism; D026502:LDL-Receptor Related Proteins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008875:Middle Aged; D009765:Obesity / Q000235:genetics*; D011972:Receptor, Insulin / Q000378:metabolism*; D011973:Receptors, LDL / Q000378:metabolism*; D012307:Risk Factors; D015398:Signal Transduction; D014280:Triglycerides / Q000378:metabolism; D055815:Young Adult
D015703:Antigens, CD; D007328:Insulin; D026502:LDL-Receptor Related Proteins; D026901:Membrane Transport Proteins; D011973:Receptors, LDL; C102582:SORL1 protein, human; C491168:Sorl1 protein, mouse; D014280:Triglycerides; C435941:INSR protein, human; D011972:Receptor, Insulin; D005947:Glucose