Insulin resistance, obesity, impairs cognition, study says

Obesity can break down the protective blood-brain barrier, resulting in problems with learning and memory, according to a new study published in The Journal of Neuroscience.

Obesity and insulin resistance elicit blood-brain barrier breakdown in humans and animal models, but the relative contributions of the two pathologies remain poorly understood.

Researchers from the Medical College of Georgia in Augusta looked at the temporal progression of cerebrovascular dysfunction relative to dietary obesity or diet-induced insulin resistance in male mice. They found obesity increased blood-brain barrier permeability to the low molecular weight fluorophore sodium fluorescein (NaFl), while diet-induced insulin resistance increased permeability to both NaFl and Evans Blue, which forms a high molecular weight complex with serum albumin, according to the study abstract.

Analysis of hippocampal capillaries revealed that diabetes promotes involution of tight junctions, fenestration of endothelial cells, and pericyte regression. In addition, chronic activation of adenosine receptor 2a (Adora2a) erodes tight junctions between endothelial cells of the cerebral vasculature in other models of chronic neuropathology, and researchers observed that acute Adora2a antagonism normalized blood-brain barrier permeability in mice with diet-induced insulin resistance.

Experiments in mice with inducible deletion of Adora2a in endothelial cells revealed protection against blood-brain barrier breakdown with diet-induced insulin resistance, despite comparable metabolic dysfunction relative to nontransgenic littermates. Protection against breakdown was associated with decreased vascular inflammation, recovery of hippocampal synaptic plasticity, and restoration of hippocampus-dependent memory, researchers say.

The findings indicate that Adora2a-mediated signaling in vascular endothelial cells disrupts the blood-brain barrier in dietary obesity and implicate cerebrovascular dysfunction as the underlying mechanism for deficits in synaptic plasticity and cognition with obesity and insulin resistance.

Future research will likely include figuring out where the signal arises that chronically activates Adora2 in fat mice, researchers say.