Sugar has a bittersweet reputation when it comes to health. Naturally occurring sugars in fruits, vegetables, grains, and dairy are part of a healthy diet. These foods are digested slowly, offering a steady supply of energy to our cells. The problem arises with extra sugars—those added to foods during processing to enhance flavor or increase shelf life. Excess consumption of added sugars is linked to metabolic disorders like obesity and diabetes, which in turn raise the risk of neurodegenerative diseases.
In an earlier study, Dr. Akhila Rajan, an Associate Professor in the Basic Sciences Division at Fred Hutch, and her team explored how obesity contributes to neurodegenerative diseases. Using the fruit fly model, they discovered that a high-sugar diet causes insulin resistance in glial cells—brain support cells responsible for clearing out damaged neurons. The team found that glia in flies fed a high-sugar diet had reduced levels of PI3K, a protein that regulates insulin sensitivity. They also had lower levels of Draper, a receptor required for glia to clear neuronal debris. As a result, glia cells were less able to "take out the trash" in the brain, leading to buildup that could harm neurons and increase the risk of neurodegeneration.
In a recent paper, Dr. Rajan’s lab discovered new ways that high-sugar diet disrupts glial cells function. A high-sugar diet disrupts fat cell metabolism and, in turn, impairs the brain's cleanup system[SD1] . “This research demonstrates for the first time that changes in fat tissue induced by high-sugar diets can impair the function of phagocytic cells in the brain,” Dr. Rajan said. “It shows that peripheral lipid metabolism and mitochondrial state can remotely influence neuroimmune surveillance, offering insights into how metabolic disorders may elevate neurodegenerative risk.”
It turns out that fat tissue doesn’t just store energy—it also acts as a communication hub, constantly sending and receiving signals to and from the brain. Fat cells release special molecules called adipokines to relay these messages. When that communication breaks down, glial cells may stop functioning properly.
Using fruit flies, the Rajan lab found that fat cells communicate with glia via ApoB lipoproteins—fat-carrying particles that help glia produce Draper. Without enough ApoB signaling, glia can’t express Draper properly, and cleanup of brain debris declines. The researchers also examined phosphatidylethanolamine (PE), a fat carried by ApoB lipoproteins. Draper binds to PE, which helps activate glial cleanup. But high-sugar diets reduce PE levels, further weakening glial function.
Surprisingly, when exposed to high dietary sugar intake for a long time, fat cells start acting like the body is starving. In actual starvation, fat cells burn stored fat for energy. In a similar way, high-sugar diets push fat cells to rely more on fat-burning than sugar metabolism. This constant fat burning creates harmful byproducts that can damage other organs, including the brain. The team also found higher levels of ketones —compounds that the body produces during starvation—suggesting that sugar overload can mimic starvation at the cellular level.
Zooming in further, the team noticed that mitochondria in fat cells changed their shape and behavior in response to a high-sugar diet. These changes likely send altered signals to glia, reducing their ability to respond to injury. While the exact messages are still unknown, these mitochondrial shifts appear to be a stress response—possibly helping fat cells survive—but at a cost to the brain.
Understanding these metabolic changes sheds light on how chronic sugar intake disrupts not just fat tissue but also brain health. Dr. Rajan’s research shows that what happens in fat doesn’t stay in fat—it can ripple into the brain, potentially affecting memory, cognition, and the risk of dementia.
[SD1]maybe emphasize more how this work is different from the previous work you mentioned in the paragraph before?
Looking ahead, Dr. Rajan’s lab is interested in exploring “analogous pathways of adipocyte-glia communication in ApoB-containing lipoproteins under different dietary conditions, and whether therapeutic modulation of ApoB or LpR1 can restore glial phagocytic capacity and improve learning and memory behaviors.”
The spotlighted work was funded by the National Institutes of Health, a Helen Hay Whitney Postdoctoral Fellowship, and the McKnight Foundation Neurobiology Disorders Award.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium member Dr. Akhila Rajan contributed to this research.
Alassaf M, Madan A, Ranganathan S, Marschall S, Wong JJ, Goldberg ZH, Brent AE, Rajan A. (2025). Adipocyte metabolic state regulates glial phagocytic function. Cell Rep.
Joss Landazuri is a PhD candidate at the University of Washington in the Microbiology program working at the intersection of biomedical science, public policy, and science diplomacy. As a Latina scientist, communicator, and policy advocate, she is passionate about leveraging her academic training, personal background, and cultural heritage to engage underserved communities in both science and the policymaking process.
For the Media