Intake of highly processed and energy-dense foods combined with sedentary lifestyles are contributing to a global obesity epidemic. The World Health Organization estimates that more than one billion people worldwide are obese, and that this number will continue to grow at an alarming rate over the coming years. This is concerning since obesity adversely affects nearly all physiological functions of our bodies. Obesity is well known to cause insulin resistance (a condition in which our bodies become less sensitive to insulin), contributing to cardiovascular disease and type II diabetes. More recently, obesity has also been linked to neurodegenerative diseases. “Several large-scale epidemiological studies found that obesity is an independent risk factor for neurodegenerative disorders,” stated Dr. Mroj Alassaf, a postdoctoral fellow in Dr. Akhila Rajan’s lab, an assistant professor in Basic Science at Fred Hutch. However, “we do not fully understand the mechanisms underlying this connection,” Dr. Alassaf added.
There is increasing evidence that microglia (brain immune cells) play crucial roles in a wide range of neurodevelopmental disorders. Their primary functions include providing nourishment and support to neurons, phagocytosing cellular debris, and responding to foreign stimuli (such as pathogens). The phagocytic function of microglia declines with age, impairing their ability to respond to insults, thus contributing to neurodegenerative diseases. Interestingly, microglia express insulin receptors (IR), suggesting insulin may directly affect microglia function. It is unclear, however, whether diet-induced changes in insulin levels affect glia function. In a recent study led by Dr. Alassaf, researchers investigated the link between "obesogenic diets and insulin resistance-induced glial phagocytic dysfunction-a key driver of neurodegenerative disease."
To study microglia phagocytosis function in response to obesogenic diets, Dr. Alassaf used Drosophila microglia-like cells called ensheathing glia. They reside in the antennal lobe region, the primary brain area responsive to olfactory stimuli, and have similar functionality to human microglia. The ensheathing glia express the homolog of the mammalian phagocytic receptor, Draper, just as they do in mammals. Draper expression is low in healthy cells and is regulated by phosphoinositide 3-kinase (PI3K), a downstream effector of IR signaling. The expression of Draper is upregulated during insults and is controlled by the transcription factor Stat92E, another downstream target of IR signaling. First, the authors investigated if glycolysis and oxidative phosphorylation (two major metabolic pathways that provide energy to cells) were altered in ensheathing glia underhigh-sugar diets (HSD) and normal diets (ND). They found that the expression of the Lactate dehydrogenase (LDH) enzyme, responsible for glycolysis final steps, was attenuated in HSD glia cells. Furthermore, mitochondria morphology did not change, indicating no alteration in mitochondria oxidative phosphorylation. This is significant since activated microglia rely heavily on glycolysis for metabolic energy. In contrast, the authors observed an increase in lipid droplet accumulation in the HSD treatment as compared to control, which has been linked to alterations in the insulin signaling pathway. The authors demonstrated that HSD treatment causes insulin resistance in ensheathing glia, by describing how under HSD conditions insulin inhibits IR activation, reducing PI3K activation and inhibiting Draper, an engulfment receptor necessary for glial phagocytosis. Together, this suggests that HSD downregulates Draper expression by inducing glial insulin resistance.
The authors then asked whether HSD treatment prevents Draper's upregulation after neuronal injury. Since ensheathing glia cells are localized in the olfactory region, the authors injured olfactory neurons to promote phagocytosis of the damaged neurons by ensheathing glia. Despite neuronal damage, the expression of Draper did not increase in the ensheathing glia. Additionally, the authors examined Stat92E, a transcription factor that upregulates the Draper gene. HSD treatment reduced Stat92E levels at baseline and inhibited post-injury upregulation as expected. Their results demonstrated that chronic HSD impairs the Stat92E/Draper signaling pathway, leading to impaired glial phagocytosis.
Together, these data suggest that diet-induced obesity alters glial function, increasing the risk of neurodegenerative diseases. Next, Dr. Alassaf aims to “compare the changes caused by obesogenic diets and aging on the whole brain transcriptome.” “Our findings imply that dietary interventions could prevent or counteract glial dysfunction associated with aging, potentially reducing age-related cognitive decline,” she concluded.
The spotlighted research was funded by the National Institute of General Medical Sciences, the Brain Research Foundation, and the Helen Hay Whitney Foundation.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium member Akhila Rajan contributed to this study.
Alassaf M, Rajan A. Diet-Induced Glial Insulin Resistance Impairs the Clearance Of Neuronal Debris. bioRxiv [Preprint]. 2023 Mar 10:2023.03.09.531940. doi: 10.1101/2023.03.09.531940.