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Study maps a molecular link between insulin-sensitivity and obesity.

Obesity is a global health problem that poses a major risk factor for life-threatening diseases such as cardiovascular disease, cancer, and neurodegeneration. Recent studies have identified specific loci associated with obesity in humans, paving the way for potential therapeutic strategies to combat metabolic disorders.  One such example is SORL1, the gene encoding sorting-related receptor with type A repeats (SORLA).  The link between certain hereditary forms of the SORLA gene, larger waist circumferences and increased levels of body fat was only known from genetic studies.  However, the molecular mechanisms of many loci associated with metabolic traits remain poorly understood, mandating functional studies to elucidate their mode of action.  Now, a study led by researchers from the Max Delbrück Center identifies a role for this receptor in the control of lipid turnover in adipose tissue and a rise in insulin sensitivity.  The team state that their findings suggest adipose tissue that is overly sensitive to insulin only becomes a problem if the person has an unhealthy diet.  The opensource study is published in The Journal of Clinical Investigation.

Previous studies show that SORLA is a protein which influences the balance of metabolic processes in adipose tissue, a particular form of fat. Too much of it makes fat cells overly sensitive to insulin, which leads them to break down less fat.  SORLA is part of a machinery within cells that sorts proteins to processing where they are either broken down or flagged for recycling. SORLA was previously known for its protective role in Alzheimer’s disease, where SORLA reduces levels of proteins that form dangerous deposits.  The current study provides 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.

The current study analyzes the adipose tissue of 362 overweight people, to show that the more SORLA people have in their fat, the more overweight they will be.  The lab establish a causal link by conducting experiments on mice with a form of the SORLA gene that produced high levels of the protein only in adipose tissue.  Results show that when the animals began eating high-calorie food, they quickly became obese. Data findings, by contrast, show that mice with a deactivated SORLA gene, who ate the same food, were markedly thinner than mice with normal SORLA levels.

Results show that cells with an excess of SORLA clearly reacted more strongly to insulin, with studies on cell cultures allowing the researchers to follow SORLA and the receptor molecules that cells use to detect insulin on their way through the cell’s sorting stations. Data findings show that SORLA marked the insulin receptors for recycling and prevented them from being broken down in compartments called lysosomes.

The group observed that with higher levels of SORLA, more insulin receptors reached the surface of the cell. They go on to explain that the higher number of receptors meant that more insulin molecules could bind to the cell, making it oversensitive to the hormone; this causes the cell to break down less fat than it should.  They also note that when mice ate normal food, their weight didn’t change much whether they had normal, excessive, or low levels of SORLA. Findings show mice with too much SORLA only gained extreme amounts of weight when they ate a diet high in fat and carbohydrates, suggesting that insulin sensitivity reacts badly to an unhealthy diet.

The team surmise that their findings show an entirely new route by which insulin signals are passed within cells, which will likely be significant in treating people with the disease.  They go on to add that disruptions in the metabolic processes triggered by insulin are a feature of diabetes.  For the future, the researchers state that they now plan to clarify how SORLA affects energy homeostasis and the occurrence of obesity.

Source: Max Delbrück Center for Molecular Medicine

 

Fat tissue of the mouse high levels of SORLA (left) normal levels of SORLA (middle). In comparison, the individual fat cells with excessive SORLA appear much larger. Right picture: Fat cells with insulin receptor marked red, early endosomes green, nuclei blue and lipid droplets white.  Credit: Vanessa Schmidt/MDC.
Fat tissue of the mouse high levels of SORLA (left) normal levels of SORLA (middle). In comparison, the individual fat cells with excessive SORLA appear much larger. Right picture: Fat cells with insulin receptor marked red, early endosomes green, nuclei blue and lipid droplets white. Credit: Vanessa Schmidt/MDC.

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