Obesity triggers neurodegeneration by inducing brain insulin resistance

In a pivotal study conducted by Mroj Alassaf and colleagues at the Fred Hutchinson Cancer Research Center in the United States, a novel connection between obesity and the onset of neurodegenerative diseases, such as Alzheimer’s, has been uncovered.

The research, employing the biological model of the common fruit fly, indicates that diets high in sugar, which are commonly associated with obesity, lead to insulin resistance within the brain. This resistance hampers the brain’s capacity to eliminate cellular waste, which in turn elevates the risk of neurodegenerative conditions.

The findings, released on November 7 in the open-access publication PLOS Biology, promise to be influential in the development of medical interventions aimed at mitigating the chances of neurodegenerative disease onset.

While the correlation between obesity and neurodegenerative diseases like Alzheimer’s and Parkinson’s has been acknowledged in scientific circles, the causal mechanisms at play have eluded researchers until now.

The team’s research delved into this conundrum by leveraging the genetic and physiological parallels between fruit flies and humans. Building on prior knowledge that a diet rich in sugar instigates insulin resistance in the peripheral tissues of fruit flies, the focus now shifted to their neural tissues. The study zoomed in on glial cells, as abnormalities in microglia are recognised contributors to neuronal decay.

The study measured the protein PI3k—a biomarker for insulin sensitivity in cells. The high-sugar diet was found to diminish PI3k levels in glial cells, suggesting a state of insulin resistance. The team also examined the fruit fly’s version of microglia, known as ensheathing glia, responsible for clearing out neuronal waste, including deteriorating axons.

These glial cells exhibited depleted levels of Draper, a protein integral to their waste-removal function, indicating a compromised ability. Subsequent experiments demonstrated that artificially reducing PI3k levels not only caused insulin resistance but also led to decreased Draper levels in the ensheathing glia. Moreover, when the team inflicted damage on olfactory neurons, the ensheathing glia of sugar-fed flies failed to clear the resulting neuronal debris due to their unresponsive Draper levels.

The researchers conclude by stating that their work with fruit flies has established that high-sugar diets induce insulin resistance in glial cells, which disrupts their neuronal cleanup role. This study sheds light on the potential pathways through which diets leading to obesity may elevate the risk of neurodegenerative diseases.