Microglial heterogeneity in obesity

Obesity prevalence has increased rapidly in recent years, reaching pandemic proportions. Prolonged intake of a hypercaloric diet is associated with chronic inflammation in the periphery, but also in the central nervous system. In the brain, microglia are the immune cells responsible for maintaining homeostasis, thus ensuring correct neuronal function. While it is well understood that microglia get chronically activated in obesity, little is known about any brain region and sex differences, and the effect of the time-of-day on microglial function. In our work, we evaluated microglial heterogeneity and tested novel approaches in the study of microglia in obesity.
We performed the majority of our work in control and obese mice or rats, evaluating the changes taking place in microglia. We found in rats that obesity induces changes in microglial daily rhythmicity, affecting their circadian, immune and metabolic function, and this often occurred in the inactive period of the animals, highlighting a shift compared to physiological state. We performed a literature review and found clear differences in microglial function in obesity dependent on brain region localization, sex and age. We found in obese mice with specific deletion of the insulin receptor in microglial cells that insulin plays an important role in microglial function and that role is sex-dependent. Moreover, the use of novel state-of-the-art experimental approaches such as ultrasensitive proteomics and thermal proteome profiling allowed us to explore microglial signaling pathways in response to insulin or immunometabolism-regulating drugs. In summary, we found that microglial heterogeneity plays an important role in obesity.