Genetic variations in the expression of the protein, sortilin-related receptor, L (SORL1), are known risk factors for the development of obesity. However, the mechanisms behind the link were – until now – unknown.
Enter the new study, which suggests SORL1 influences fat accumulation by altering insulin signalling.
Greater insights into how genetic variations in SORL1 alter metabolism to increase body mass could point the way towards preventative strategies for obesity and related disorders, said the team, led by Professor Thomas Willnow from the Max Delbrück Center for Molecular Medicine in Germany.
The findings also confirm a beneficial genetic link between neurodegeneration and metabolism that is mediated by SORL1, the team claim.
Previous studies have shown the expression of SORL1 can reduce the level of proteins which form amyloid plaques – a common symptom of the disease.
“Obesity is a global health problem that poses a major risk factor for life-threatening diseases such as cardiovascular disease, cancer, and neurodegeneration,” the team said.
They noted that recent genetic epidemiology, a genome-wide association (GWAS) studies have identified gene loci associated with obesity in humans which paved the way for potential therapeutic strategies to combat metabolic disorders.
“Our findings provide a molecular mechanism for the association of SORL1 with human obesity and confirm a genetic link between neurodegeneration and metabolism.”
The team note that over-expression of SORL1 in fat tissues encourages fat storage by blocking the breakdown of triacylglycerides (stored fats) into free fatty acids (FFAs).
“In contrast, SORL1 gene inactivation accelerates FFA release from triacylglycerides and protects mice from diet-induced obesity,” they added. The study included data from mice and humans.
“SORLA (SORL1) facilitates functional expression of the insulin receptor (IR) to promote insulin-dependent suppression of lipolysis in adipocytes,” said the team – noting that a high expression of SORLA makes fat cells overly sensitive to insulin, which leads them to break down less fat.
Specifically, Willnow and his team found that SORL1 acts as a ‘sorting factor’ for insulin receptors within fat cells and redirects internal insulin receptor molecules to the outer cell membrane - thereby enhancing surface expression insulin receptors and strengthening insulin signal reception in fat cells.
Source: Journal of Clinical Investigation
Published online, Open Access, doi: 10.1172/JCI84708
“SORLA facilitates insulin receptor signaling in adipocytes and exacerbates obesity”
Authors: Vanessa Schmidt, et al