Mapping of Microglial Brain Region, Sex and Age Heterogeneity in Obesity

Abstract

The prevalence of obesity has increased rapidly in recent years and has put a huge burden on healthcare worldwide. Obesity is associated with an increased risk for many comorbidities, such as cardiovascular diseases, type 2 diabetes and hypertension. The hypothalamus is a key brain region involved in the regulation of food intake and energy expenditure. Research on experimental animals has shown neuronal loss, as well as microglial activation in the hypothalamus, due to dietary-induced obesity. Microglia, the resident immune cells in the brain, are responsible for maintaining the brain homeostasis and, thus, providing an optimal environment for neuronal function. Interestingly, in obesity, microglial cells not only get activated in the hypothalamus but in other brain regions as well. Obesity is also highly associated with changes in hippocampal function, which could ultimately result in cognitive decline and dementia. Moreover, changes have also been reported in the striatum and cortex. Microglial heterogeneity is still poorly understood, not only in the context of brain region but, also, age and sex. This review will provide an overview of the currently available data on the phenotypic differences of microglial innate immunity in obesity, dependent on brain region, sex and age.

Loss of Microglial Insulin Receptor Leads to Sex-Dependent Metabolic Disorders in Obese Mice

“…Up until recently, rodent studies on metabolic disorders mainly focused on males and sex differences have been understudied, especially concerning microglia. However, emerging data are pointing to a strong heterogeneity of microglia between males and females [ 40 , 41 ]. A study by Dorfman et al, showed that a sex-specific CX3CR1 hypothalamic signaling is at the core of obesity progression, with female mice maintaining a level of resistance to DIO [ 42 ].…”

“…In summary, the findings of this study highlight the importance of microglial insulin signaling in the CNS control of energy metabolism and the sex-dependent differences observed during the progression of obesity. Microglial cells seem to show a vast difference in their phenotype between males and females in an age-, region-, and disease-dependent manner [ 40 , 41 , 44 ]. Our findings provide further insight into the complex mechanisms that are operative in the brain for the control of energy metabolism in health and disease and highlight the importance of taking into account possible sex-dependent differences in these mechanisms.…”

The Obese Brain: Mechanisms of Systemic and Local Inflammation, and Interventions to Reverse the Cognitive Deficit

“…HFD increases Iba-1 expression in the arcuate nucleus (ARC), paraventricular nucleus (PVN), and hippocampus. No specific microglial changes are observed in the cerebral cortex and striatum ( Thaler et al, 2012 ; Milanova et al, 2021 ). In the medio -basal hypothalamus (MBH), microgliosis is mediated by activating pathways such as NF-κB, favoring cell infiltration, increased food intake, and local inflammation ( Valdearcos et al, 2017 ).…”

“…However, evidence has begun to emerge that systemic inflammation, either induced with peripheral LPS or the administration of one or more of the pro-inflammatory cytokines such as TNFα, IL1β, IL6, IL33, is involved in microglial priming ( Perry and Holmes, 2014 ; Li J. W. et al, 2018 ). Due to the heterogeneity of microglial density depending on the brain region, brain structures are differentially affected; the main affected brain regions are the hypothalamus, hippocampus, cerebral cortex, and striatum ( Milanova et al, 2021 ). Another example is the NLRP3 protein of the inflammasome in visceral adipose tissue, which directly affects IL1ß levels in the brain, activating microglia through the IL1R1 receptor and thus affecting memory in obese animals ( Guo et al, 2020 ).…”

Biogenic Amine Levels Markedly Increase in the Aqueous Humor of Individuals with Controlled Type 2 Diabetes

“…Another concern derives from the neurological alterations associated with diabetes that affect cognitive functions, but also sensory and motor control functions [ 7 ]. The neurological manifestations are due to functional and structural alterations, some of which present variable degrees of microglial activation [ 8 , 9 , 10 , 11 ]. For ethical reasons derived from the invasiveness of obtaining it, cerebrospinal fluid (CSF) has not been extensively studied in diabetic patients.…”