Figure 1.

Overview of peripheral and central insulin actions. Insulin action primarily originates from the pancreas, the site of insulin production, and can act on many target tissues (black arrows). In the periphery, insulin has actions in all tissues, but predominantly affects major metabolic tissues, such as the adipose tissue, liver, and skeletal muscle. Insulin crosses the blood–brain barrier (BBB) to act within the central nervous system (CNS) to regulate both direct effects within the brain as well as elicit indirect signaling events back to the periphery. Insulin can also signal at the brain endothelial cell to regulate BBB function. On the other hand, apolipoprotein E (apoE) has distinct pools (peripheral and central), as apoE does not cross the BBB, with liver and brain producing the majority of these apoE pools. There is still crosstalk between these two pools as peripheral apoE can still readily affect central apoE, and vice versa, through indirect actions (i.e., via the gut microbiome and gut-liver-brain axis). Created with Biorender.com software.