A compelling new study from scientists at the Fred Hutchinson Cancer Research Center is pointing to a possible mechanism linking obesity with neurodegenerative diseases. The detailed work in fruit flies suggests diet-induced insulin resistance can impair the brain’s ability to clear out neuronal debris and contribute to the development of diseases such as Alzheimer’s.
The relationship between obesity and dementia is still not entirely clear. Several large-scale epidemiological studies in recent years have delivered frustratingly inconsistent results. A major 40-year study following nearly 20,000 men reported a strong link between higher body weight and risk of death from dementia. However, another significant study looking at 20 years of data from nearly two million people came to a different conclusion, finding being underweight in middle-age was associated with an increased risk of dementia in old age.
Underpinning these contradictory findings is the mystery of how exactly obesity could directly contribute to neurodegeneration. One school of thought suggests obesity may not directly influence dementia but instead the secondary lifestyle effects of being overweight (poor diet, lack of exercise etc) are what negatively affect brain health.
To better understand how obesity could trigger neurodegeneration, researchers often look to a type of small fruit fly called Drosophilia. As researcher Akhila Rajan explains to New Atlas, these fruit flies offer scientists a useful way to model the physiological impact of weight gain in humans.
"Flies consume sugars from fruits," says Rajan. "By increasing the amount of sugar in standard lab diets they gain 'weight' – in terms of fat stores. We find that when we feed flies a high-sugar diet, it triggers remarkable physiological changes that mirror the effects of type 2 diabetes in humans including insulin resistance. Hence, flies fed high sugar diets serve as a great model for understanding what goes wrong in humans."
Fruit flies also harbour brain immune cells with insulin sensitivities that are similar to what we see in human brains. So feeding the insects a high-sugar diet offers researchers a helpful way to study the effects of diet and insulin on key brain cells.
The key hypothesis at play in this new research surrounds a process called phagocytosis. This is an essential cellular mechanism for clearing out both pathogens and dead or dysfunctional particles. It is generally believed that in humans most dementia-related diseases are somewhat caused by the brain’s increasing inability to clear out toxic proteins in the brain. Alzheimer’s disease, for example, is characterized by increasing clusters of damaging amyloid proteins which, in a healthy brain, would normally be cleared out by immune cells called microglia.
The big question explored in this new research is whether a high-sugar diet directly influences the brain’s ability to clear out this toxic neuronal debris. And using a fruit fly model, Rajan and study co-author Mroj Alassaf have elegantly demonstrated this is certainly the case. The study demonstrated a high-sugar diet impairs the fly’s glial cells’ ability to remove neuronal debris. And while of course this is a study only working with fruit flies, Rajan is confident this mechanism could be transferable to humans.
"While it's important to acknowledge that fly glial cells and human glial cells exhibit structural and functional differences, it's worth noting that in vitro studies have revealed that human glia are sensitive to insulin and respond accordingly," Rajan says to New Atlas. "This intriguing finding opens the door to the possibility that the mechanism we're uncovering in fly glial cells might share some common features with their human counterparts."
Suzanne Craft, a researcher from the Wake Forest School of Medicine, has long investigated the role of insulin in the brain. She did not work on this new study but calls the mechanisms highlighted "intriguing" and suggests they may help explain some of epidemiological work in humans linking poor diet with Alzheimer’s risk. Craft is cautious to stress the importance of better understanding how these fruit fly findings translate to humans but does indicate there is good evidence to suggest impaired insulin signaling plays a role in conditions such as Alzihemer’s disease (AD).
"In relevant studies, we have documented that normal middle aged adults who consumed a Western diet for one month had impaired insulin signaling and pathological changes in AD amyloid markers in cerebrospinal fluid," Craft tells New Atlas in an email. "Further, insulin signaling plays a critical role in many aspects of immune function that moderate inflammation and are mediated by microglia and astrocytes in humans. Thus conditions which induce insulin resistance such as obesigenic diets may adversely impact immune function and AD pathology."
So, if this obesity-induced neurodegeneration is translatable to humans what future therapeutic options, could we develop to better treat dementia diseases? Beyond everyone losing weight and eating better perhaps the most straightforward possibility would be simply increasing circulating insulin levels?
Interestingly, there is ongoing research exploring that very option. In fact, a recent Phase 2 clinical trial looked at testing an intranasal insulin spray designed to deliver the hormone directly to the brain. The idea is cognitive health could be improved by improving insulin signaling in the brain, and early results have been mildly promising.
Rajan, however, is unsure if directly increasing insulin levels will help improve brain health, at least in terms of restoring phagocytosis. She suggests her work has shown genetically increasing circulating insulin levels have led to other kinds of glial dysfunction. So the solution may be to look further down the chain of insulin signaling.
"Metformin – a well-known AMPK inhibitor – stands out as the most well-established drug for treating type 2 diabetes and has the unique ability to cross the blood-brain barrier," Rajan says. "However, current research findings present a complex picture regarding whether metformin treatment benefits or harms neuronal health and survival. Notably, these effects appear to vary based on factors such as dosage and treatment duration."
There certainly are studies that have found links between metformin use and lower rates of cognitive decline. Exactly how this works is still unclear, and it’s unlikely metformin will be the specific solution to dementia prevention. But what these new findings definitely do are gesture towards ways that neurodegeneration could be prevented by better understanding the intricate molecular mechanisms at play.
The new study was published in PLOS Biology.
