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Insulin resistance turns tidy brain cells into slobs — which could be a link between diet and neurodegenerative diseases

BY SABRINA RICHARDS / FRED HUTCH NEWS SERVICE

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These findings show how eating processed food doesn’t just affect weight gain, it affects cognitive function, and a deep functioning of your body.

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07/11/23 - Fred Hutch Cancer Center

Neurons like it tidy. Brain cells called glia help neurons perform at their best by cleaning up toxic cellular debris. But a diet high in sugar makes glia insulin resistant — which turns them into apathetic housekeepers that let damaging debris pile up, according to new work from Fred Hutchinson Cancer Center scientists, published in the journal PLOS Biology. The findings in fruit flies could help explain how diet influences risk of neurodegenerative disorders like Alzheimer's disease.
 
“These findings show how eating processed food doesn’t just affect weight gain, it affects cognitive function. It affects a deep functioning of your body,” said Fred Hutch obesity researcher and senior author Akhila Rajan, PhD. “Our study provided missing evidence that glial insulin resistance has consequences to glia’s debris-clearing role.”
 
In the new work, Rajan Lab postdoctoral fellow Mroj Alassaf, PhD, confirmed that, like peripheral tissues, brain cells can become insulin resistant. Alassaf demonstrated that the high levels of insulin induced by excess dietary sugar causes glial dysfunction, which prevents glial cells from cleaning up damaging cellular debris.
 
“We found that it’s not about weight, it’s about insulin signaling,” Alassaf said.
 
While mid-life obesity has been linked to greater risk of later-life dementia, her findings suggest that it may be possible to keep brain cells healthy by focusing on improving insulin sensitivity.
 

A missing mechanism

Our diet, weight and metabolic health connect to our risks of other diseases, including cancer and neurodegenerative diseases, in ways that are difficult to untangle.
 
“Obesity is an independent risk factor for dementia, but the causative mechanism underlying that connection is largely unknown,” Alassaf said.
 
What is known is that malfunctioning of glial cells, which tidy up debris and influence neuron function by “pruning” nerve cells, can contribute to neurodegeneration. Studies have shown that changes in glial cell function can alter animals’ weight, metabolism and feeding behaviors. Whether glia can become insulin resistant, and whether this could cause changes in their function, was also unknown.
 
To study the effects of insulin on glial cells, Rajan and Alassaf turned to fruit flies. They’re an attractively simple organism in which to study how diet and adipose tissue influence health. Like us, fruit flies have an insulin-like hormone that helps regulate energy storage and energy-dependent behaviors like sleep, reproduction and food foraging. And like us, these tiny creatures bump up their lipid stores when they eat too much sugar for too long. (Yes, even fruit flies can eat too much sugar, although their exoskeletons limit the amount of new lipids they can amass.)
 
The time scale’s a little different, though: Flies become insulin resistant after just a couple of indulgent weeks. Insulin resistant cells need more insulin to wedge open the molecular “doors” that let sugar in. Insulin resistance is closely related to prediabetes and metabolic syndrome, and it’s a risk factor for developing type 2 diabetes and cardiovascular disease.
 
A team of Rajan Lab postdocs, including Alassaf, had already mapped out the timeline of flies’ “metabolic collapse” in a paper published last year in eLife. She decided to use the same experimental approach to study whether these diet-induced metabolic changes affect glia.
 
While insect glia and human glia aren’t exactly the same, glia in both organisms do the critical work of clearing up debris that can be damaging to neurons. These debris include cellular detritus released by neurons themselves, as well as the misfolded proteins that build up in neurodegenerative conditions like Alzheimer’s.
 
“What happens in these conditions is that glia become less efficient in clearing up these cytotoxic [cell-damaging] debris,” Alassaf said. “Leaving that debris behind induces inflammation, it induces secondary cell death — so clearing it up is a pretty crucial step in remedying damage.”
 

Too much sugar makes glia insulin resistant

Alassaf asked a simple question: If fruit flies spend a prolonged period eating a high-sugar diet known to make them obese, what happens to the insulin responsiveness of their glia?
 
In Rajan’s team’s previous study, the researchers had seen that flies developed insulin resistance in peripheral (non-brain) tissues after just two weeks of a diet containing 30% more sugar than normal. In the current study, Alassaf fed the flies the sugary diet for three weeks (about one-third of the average fly lifespan) and then compared the insulin sensitivity of their glia to the glia of flies that continued eating a standard diet.
 
Over time, flies overfed sugar increased their insulin levels to handle the extra sugar. Alassaf saw that despite this, their glia became less responsive to insulin than normal. The glia had become insulin resistant.
 
Glia use a cleanup protein called Draper to vacuum up nearby debris. After neuronal damage creates more debris, glia boost the levels of Draper to handle the extra cellular waste. Alassaf found that insulin-resistant glia had lower-than-normal levels of Draper, and that they didn’t ramp it up after nerve cell damage.
 
“We saw that at four days, when normal glia have done their job and cleared the debris, this neuronal debris persists much longer in flies with insulin-resistant glia,” Alassaf said.
 
As over-sugared flies’ insulin jumps, they also store the excess energy as fat, which can communicate with brain cells. To untangle the influence insulin and fat on glia, Alassaf genetically engineered flies to release extra insulin even when she kept the sugar in their diets at a normal level. This mimicked the insulin levels of flies eating a high-sugar diet — without the sugar. Alassaf showed that glia in these genetically manipulated flies turned down Draper. When she genetically manipulated fruit flies to keep their insulin levels low even when they ate excess sugar, their glia remained insulin sensitive, and Draper levels remained normal.
 
This shows that flies’ diet-induced glial dysfunction resulted from their insulin response, not their fat stores, she said.
 

A complex biological response to diet

The different timescales at which the brain and peripheral tissues become insulin resistant should inspire scientists to take a wider view of how diet affects health, Rajan said: “In humans, we think primarily of weight gain, but by increasing sugar in the diet, we’re impacting each cell differently.”
 
Alassaf’s next steps will be two-pronged. First, she’ll continue exploring the biology behind insulin’s effects on glia. Insulin-resistant glia appear to experience a shift in how they generate energy, which could prevent their activation. In the previous work, Rajan’s team had showed that certain lipids are more toxic to health than others. Glia also store lipids, and Alassaf wants to see how these lipids affect glial and neuronal function.
 
She also wants to test how insulin-resistant,impaired glia affect fly behavior. While flies don’t get dementia, she test whether insulin resistance in their brain affects their performance on tests of learning and memory, and whether improving their insulin sensitivity can also improve their scores.
 
The good news for anyone who’s worried about how mid-life obesity or weight gain may affect their risk of dementia later is that insulin resistance is reversible, Rajan noted. It can be improved with changes to dietary and activity habits. There are already hints that medical interventions that improve insulin sensitivity, like the diabetes drug metformin, can protect against dementia — and Alassaf’s work supports investigating this further, Rajan said.
 
“As a scientist, what you want to do is not just find a cause, but also provide an intervention,” she said.