Brain Insulin Resistance and Microglial Dysfunction Link Obesity with Neurodegenerative Disorders

Researchers at Fred Hutchinson Cancer Research have discovered a link between obesity and neurodegenerative disorders such as Alzheimer’s disease. Studies in the fruit fly Drosophila demonstrated that a high-sugar diet—a hallmark of obesity—causes insulin resistance in the brain, impairing the phagocytic function of glial cells and reducing their removal of neuronal debris, which then increases the risk of neurodegeneration. Reported in PLOS Biology, the results could impact future therapies that are designed to reduce the risk of developing neurodegenerative diseases.

Research lead Mroj Alassaf, PhD, and colleagues described their findings in a paper titled, “Diet-induced glial insulin resistance impairs the clearance of neuronal debris in Drosophila brain,” in which they concluded that their study offers “the first in vivo evidence of diet-induced regulation of glial phagocytic function … Together, our study provides a strong mechanistic insight into how diet-induced obesity alters glial function, thereby increasing the risk of neurodegenerative disorders.”

The leading cause of obesity is a high-sugar diet (HSD), and while obesity is known to be a risk factor for neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease, exactly how one leads to the other remains a mystery. One key feature of neurodegenerative disorders is diminished clearance of neuronal debris, the authors noted. “Microglia are the brain’s resident macrophages. When activated, they can swiftly mobilize to the site of disease or neuronal injury and initiate phagocytosis.” However, chronic activation of microglia can result in a progressive decline in their phagocytic capacity, which is evident in the aging brain. And microglial dysfunction is known to lead to neural degeneration. “Interestingly, obese humans and animals also display chronic activation of microglia, which has been shown to contribute to neuroinflammation,” the authors continued. “However, little is known about the effects of obesity on glial phagocytic function. Uncovering whether and how diet-induced obesity disrupts glial phagocytosis may shed some light on the link between obesity and neurodegenerative disorders.”

For their newly reported study, the researchers took advantage of the similarity between humans and fruit flies to investigate the link between obesity and glial cell function. The team’s research had previously shown that a high-sugar diet leads to insulin resistance in the peripheral organs of flies, and their new studies focused on the fruit fly brain, and glial cell function, in animals fed using a previously established HSD regimen.

Levels of the protein PI3k indicate how much a cell is able to respond to insulin, and the team’s studies showed that the high-sugar diet led to reduced PI3k levels in glial cells, indicating insulin resistance. In Drosophila, microglial cells known as ensheathing glial act as the brain’s resident phagocytes whose primary function is to remove neural debris, such as degenerating axons. “Analogous to mammalian microglia, ensheathing glia respond to neuronal injury by extending their membrane processes towards the site of damage and initiating phagocytic activity,” the team stated.

Akin to their mammalian counterparts, Drosophila ensheathing glia express phagocytic receptors, and most prominently mammalian multiple EGF-like domains 10 (MEGF10) homolog known as Draper. “Several studies have demonstrated that baseline levels of Draper in the uninjured brain determine the phagocytic capacity of ensheathing glia,” they continued. “Upon injury or disease, ensheathing glia up-regulate Draper.”

Through their newly reported experiments, the team observed that the Drosophila ensheathing glia had low levels of Draper, indicating impaired function. In further tests, the team showed that artificial reduction of PI3k levels led to both insulin resistance and low Draper levels in ensheathing glia. Constitutive activation of systemic insulin release from Drosophila insulin-producing cells (IPCs) mimicked the effect of diet-induced obesity on glial Draper expression, they reported. In contrast, genetically attenuating systemic insulin release from IPCs rescued diet-induced glial insulin resistance and Draper expression. And significantly, the scientists wrote, “We show that genetically stimulating phosphoinositide 3-kinase (Pi3k), a downstream effector of insulin receptor (IR) signaling, rescues high-sugar diet (HSD)-induced glial defects.” Finally, the investigators showed that after actually damaging olfactory neurons, the ensheathing glia could not remove the degenerating axons in the flies on the high-sugar diet because their Draper levels did not increase.

“Here, using a Drosophila in vivo model, we draw a causal link between diet-induced obesity and impaired glial phagocytic function, a major contributor to the pathology of age-related neurodegenerative disorders,” the authors concluded.  “We show 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.”

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