Adipose tissue‐derived small extracellular vesicles and blood–brain barrier function in adults with overweight and obesity

Abstract Obesity is associated with adverse changes in brain structure and function, in part, through crosstalk between adipose tissue (AT) and the brain. AT releases small extracellular vesicles (sEV) that can cross the blood–brain barrier (BBB) and modulate multiple pathophysiological pathways, including BBB function; however, this has never been investigated. We characterized circulating adipose tissue‐derived sEV (sEV AT ) in adults with overweight and obesity and examined their effects on the BBB. The impact of adiposity and weight loss on these outcomes was also examined. sEV AT were isolated from the plasma of 29 adults (79% male; 93% White; mean age 66.2 ± 7.0 years; mean body mass index 36.0 ± 6.8 kg/m 2 ) randomized to cardiac rehabilitation (CR) alone or CR plus a behavioural weight loss intervention (CR+WL). Following characterization of sEV AT size, concentration and total protein content, we assessed their effect on BBB permeability using an in vitro model. hCMEC/D3 cells were treated with sEV AT , and transendothelial electrical resistance (TEER) was measured at 0, 24, 48 and 72 h. Our findings show that sEV AT treatment decreased TEER by 40%, with a significantly lower TEER at 72 h compared with controls (23.138 ± 1.209 vs. 28.724 ± 1.613 Ω cm 2 , p = 0.012). TEER was also lower in participants with higher body mass index and body fat. However, we found no difference in TEER between the CR and CR+WL groups and no significant intervention effects on sEV AT characteristics or TEER. In conclusion, higher plasma sEV AT concentrations in adults with overweight and obesity are associated with greater adiposity, which might contribute to reductions in BBB function.