The particular mechanisms causing the considerable increase in the risk of neurodegenerative disorders associated with obesity are still unknown. Overdosing in high-sugar foods is the main contributor to obesity and its related conditions, such as type 2 diabetes.
Obesity has a variety of consequences on organ function. A major mediating factor for these consequences is the disruption of the insulin signaling system. Insulin resistance develops when circulating insulin levels rise due to a long-term high-sugar diet (HSD).
It is commonly recognized that HSD can cause insulin resistance in peripheral organs like the liver and adipose tissue. Still, it is unknown whether the brain can experience the same kind of insulin resistance.
A new study using the Drosophila model- a common fruit fly model- has shown that a chronic obesogenic diet causes insulin resistance in the brain. This, in turn, reduces the ability to remove neuronal debris, thus increasing the risk of neurodegeneration. The study, led by Mroj Alassaf at the Fred Hutchinson Cancer Research Center in the United States, has discovered a link between obesity and neurodegenerative disorders.
Scientists found that excessive systemic insulin signaling leads to glial insulin resistance, which dampens the expression of the engulfment receptor, Draper, resulting in impaired glial clearance of degenerating axons.
In particular, the basal and injury-induced expression of the glia-associated phagocytic receptor, Draper, is down-regulated by exposure to an obesogenic diet. Constitutive activation of Drosophila insulin-producing cells’ (IPCs) systemic insulin secretion imitates the impact of an obesity-induced diet on the expression of glial Draper.
On the other hand, diet-induced glial insulin resistance and Draper expression are reversed when systemic insulin release from the IPCs is genetically attenuated. Notably, scientists demonstrate that glial abnormalities generated by high-sugar diet (HSD) can be prevented by genetically activating phosphoinositide 3-kinase (Pi3k), a downstream effector of insulin receptor (IR) signaling. They thus demonstrate that obesogenic diets hinder glial phagocytic activity and cause a delay in the removal of neural debris.
The authors add, “Using fruit flies, the authors establish that high-sugar diets trigger insulin resistance in glia, disrupting their ability to clear neuronal debris. This study provides insight into how obesity-inducing diets potentially contribute to the increased risk of neurodegenerative disorders.”
Journal 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. DOI: 10.1371/journal.pbio.3002359