Insulin resistance from high-sugar diets tied to increased neurodegeneration risk: Study

Neurodegenerative diseases, such as amyotrophic lateral sclerosis (ALS), Parkinson's disease, and Alzheimer's disease affect millions of people worldwide; about 15% of people around the world have a neurodegenerative disease. There is still no clarity on the main cause of many neurodegenerative disorders, but it is known that certain risk factors play a role.

Previous studies have shown that one risk factor for developing a neurodegenerative condition is obesity. However, there is no clarity on how obesity increases neurodegenerative disease risk. Mroj Alassaf and Akhila Rajan from Basic Sciences Division, Fred Hutch, Seattle, Washington, United States of America, have shed light on the mechanisms behind obesity and the risk of neurodegenerative disease.

The researchers, using a common fruit fly model, believed a high-sugar diet causes insulin resistance in the brain, lowering the ability of the brain to remove neuronal debris, thus raising neurodegeneration risk.

Using a Drosophila model, the researchers showed that a chronic obesogenic diet induces glial insulin resistance and impedes the clearance of neuronal debris. Specifically, exposure to obesogenic diet downregulates the basal and injury-induced expression of the glia-associated phagocytic receptor, Draper.

Constitutive activation of systemic insulin release from Drosophila insulin-producing cells (IPCs) mimics the effect of diet-induced obesity on glial Draper expression. In contrast, genetically attenuating systemic insulin release from the IPCs rescues diet-induced insulin resistance and Draper expression.

The researchers showed that genetic stimulation of phosphoinositide 3-kinase (Pi3k), a downstream effector of insulin receptor (IR) signalling, rescues glial defects inducted by a high-sugar diet (HSD). Here, they established that obesogenic diets impair glial phagocytic function and delay neuronal debris clearance.

With increased life expectancy, age-related neurodegenerative disorders are expected to rise, placing a tremendous burden on the healthcare system. Large-scale epidemiological studies have revealed that mid-life obesity is an independent risk factor for the development of neurodegenerative disorders. However, there was no clarity on the mechanism underlying this connection.

"We drew a causal link between diet-induced obesity and impaired glial phagocytic function, a major contributor to the pathology of age-related neurodegenerative disorders using a Drosophila in vivo model," the researchers wrote.

"We show that excessive systemic insulin signalling results in glial insulin resistance, dampening the expression of the engulfment receptor, Draper, leading to impaired glial clearance of degenerating axons."

"Together, our study provides a strong mechanistic insight into how diet-induced obesity modifies glial function, thereby raising neurodegenerative disorder risk," they concluded.

Reference:

Alassaf M, Rajan A (2023) Diet-induced glial insulin resistance impairs the clearance of neuronal debris in Drosophila brain. PLoS Biol 21(11): e3002359. https://doi.org/10.1371/journal.pbio.3002359