Overview of Neuroglia Activation, Chronic Neuroinflammation, Remodeling, and Impaired Cognition Due to Perivascular Adipose Tissue-Derived Extracellular Vesicle Exosomes in Obesity and Diabetes

Perivascular adipose tissue (PVAT)-derived extracellular vesicles (EVs) with small exosome(s) (PVAT-dEVexos) from the descending aorta are capable of entering capillaries and systemic circulation. These PVAT-dEVexos are delivered to the central nervous system (CNS) in preclinical, obese, insulin and leptin resistant, diabetic, db/db mouse models and humans with T2DM. Once within the CNS, these exosomes are capable of traversing the blood–brain barrier and the blood-cerebrospinal fluid barrier resulting in activation of the neuroglia microglia cell(s) (aMGCs) and the formation of reactive astrocytes (rACs). The chronic peripheral inflammation in the PVAT via crown-like structures consists of activated macrophages and mast cells, which harbor peripheral adipokines, cytokines, and chemokines (pCC) in addition to the EV exosomes. These pCC are transported to the systemic circulation where they may act synergistically with the PVAT-dEVexos to amplify the activation of neuroglia and result in chronic neuroinflammation. Once activated, the MGCs and ACs will contribute to even greater neuroinflammation via central nervous cytokines/chemokines (cnsCC). Activated neuroglia results in an increase of cnsCC and the creation of a vicious cycle of ongoing chronic neuroinflammation and increased redox stress. The increase in reactive oxygen species (ROS) involves the reactive species interactome that not only include reactive oxygen but also reactive nitrogen and sulfur species wherein a vicious cycle of ROS begetting inflammation and inflammation begetting ROS develops. Thus, the CNS perceives peripheral systemic inflammation from the obese PVAT depots as an injury and a response to injury wound healing mechanism develops with activation of neuroglia, cellular remodeling, neurodegeneration, and impaired cognition.