Study points to impairment of learning and memory due to obesity

Obesity can break down our protective blood brain barrier resulting in problems with learning and memory, a study has found. Chronic activation of the receptor Adora2a on the endothelial cells that line this important barrier in our brain can let factors from the blood enter the brain and affect the function of our neurons, scientists said. The team from Augusta University in the US have shown that when they block Adora2a in a model of diet-induced obesity, this important barrier function is maintained. “We know that obesity and insulin resistance break down the blood brain barrier in humans and animal models, but exactly how has remained a mystery,” said Alexis M Stranahan, neuroscientist at Augusta University and corresponding author of the study published in The Journal of Neuroscience.

In the brain, adenosine is a neurotransmitter that helps us sleep and helps regulate our blood pressure; in the body it’s also a component of the cell fuel adenosine triphosphate, or ATP. Adenosine also activates receptors Adora1a and Adora2a on endothelial cells, which normally supports healthy relationships between brain activity and blood flow. Problems arise with chronic activation, particularly in the brain, which is what happens with obesity, Stranahan said in a statement. People who have obesity and diabetes have higher rates of cognitive impairment as they age and most of the related structural changes are in the hippocampus, a centre of learning and memory. Fat is a source of inflammation and there is evidence that reducing chronic inflammation in the brain helps prevent obesity-related memory loss. For the study, young mice fed a high-fat diet got fat within two weeks, and by 16 weeks they had increases in fasting glucose and insulin concentrations, all signs that diabetes is in their future.

In the minute vasculature of the hippocampus, the researchers saw that obesity first increased permeability of the blood brain barrier to tiny molecules like fluorophore sodium fluorescein, or NaFl. Diet-induced insulin resistance heightened that permeability so that a larger molecule, Evans Blue, which has a high affinity for serum albumin, the most abundant protein in blood, also could get through. When they looked with electron microscopy, they saw a changed landscape. Resulting diabetes promoted shrinkage of the usually tight junctions between endothelial cells and actual holes in those cells. When they gave a drug to temporarily block Adora2a, it also blocked problems with barrier permeability. Whether that could work in humans and long term as a way to avoid cognitive decline in obese humans, remains to be seen, Stranahan said.