Neurodegenerative disorders gradually destroy the neurons and glial cells; they affect millions of individuals on a global scale and Alzheimer’s disease and Parkinson’s disease are the most common. Previously, researchers have identified obesity as a risk factor for the onset of those disorders . However, the mechanism underlying the link between obesity and neurological decline conditions remains unclear.
According to a study published in Scientific Reports in 2021, a high-sugar diet, which is a characteristic of obesity, results in insulin resistance in the brain. Insulin resistance decreases the capacity to eliminate neuronal debris, raising the likelihood of neurodegeneration
One fundamental hallmark of neurodegenerative disorders is decreased removal of neural debris. Microglia from the family of Glial cells, are macrophages that live in the brain; they can quickly mobilize to the location of disease or neuronal damage and start phagocytosis when triggered. Chronic activation of microglia may cause a steady reduction in their phagocytic function, as seen in the aging brain. Microglial dysfunction also causes neuronal degeneration.
The new research from the Fred Hutchinson Cancer Research Centre in the United States, led by Mroj Alassaf, has established a relationship between obesity and neurodegenerative disorders. The study was published in 2023 in the open-access journal PLOS Biology. The researchers used the similarities between humans and Drosophila, a common fruit fly, to analyse the association between obesity and glial cell function. The team’s previous research demonstrated that a high-sugar diet causes insulin resistance in the peripheral organs of flies. The latest investigation centered on the fruit fly brain and glial cell function in animals fed a formerly established high-sugar diet. They investigated the concentration of PI3k protein because it determines the extent of cell response to insulin: A high-sugar diet lowered PI3k levels in the glial cells, suggesting insulin resistance. The researchers further analysed the ensheathing glia, which are the counterparts of microglia in flies, and their primary role is removing neural debris, such as degenerating axons. Draper protein levels were reduced in these glia, indicating decreased function.
Similar to human microglia, ensheathing glia react to neuronal insult by expanding their membrane projections toward the point of injury starting the phagocytic function. The continuous activation of systemic insulin release from insulin-producing cells in flies replicated the impact of diet-induced obesity on the expression of glial Draper. In contrast, reducing systemic insulin release genetically affected glial insulin resistance and Draper levels. Mroj Alassaf and team demonstrated that after olfactory neuron injury in flies, the ensheathing glia in the high-sugar diet could not remove the degenerating axons because of low Draper levels.
The scientists concluded that increased systemic insulin signaling causes glial insulin resistance, which reduces Draper levels, resulting in inefficient glial clearance of degenerating axons. This study establishes a relationship between diet-induced obesity and decreased glial phagocytic activity, which contributes to the pathophysiology of age-related neurodegenerative disorders.
The findings are expected to have an impact on medications targeted to minimize the chance of acquiring neurodegenerative disorders.
References
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- Lourido F, Quenti D, Salgado-Canales D, Tobar N. Domeless receptor loss in fat body tissue reverts insulin resistance induced by a high-sugar diet in Drosophila melanogaster. Scientific Reports. 2021 Feb 5;11(1):3263. DOI: 10.1038/s41598-021-82944-4
- Alassaf M, Rajan A. Diet-induced glial insulin resistance impairs the clearance of neuronal debris in Drosophila brain. Plos Biology. 2023 Nov 7;21(11):e3002359. DOI: https://doi.org/10.1371/journal.pbio.3002359
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Image: Jessica Gray from Pixabay
