The illusion behind communication: the role of fenestrated hypothalamic blood vessels in leptin resistance
2Military Medicine and Tzameret, Faculty of Medicine, The Hebrew University of Jerusalem,
Hypothalamus regulats body fat mass and general metabolism. Hypothalamic neurons sense peripheral hormones/metabolites, distributed through the blood-stream, to activate neuro-endocrine circuites. Vasculature in the median-eminence (ME) mediates metabolic signals entry into the brain, probably credited to endothalial fenestra. We focus on mechanisms mediating leptin brain entry, and whether these are involved in development of leptin resistance. Fenestra function may be related since they are dynamic cellular structures responding to different physiological states.
We hypothesize that changes in fenestra structural/functional properties during pregnancy, aging, and obesity, might affect hormones flux into the hypothalamus. Reduced leptin availability might underlie leptin resistance. We are using functional assays, single-cell RNAseq, SEM, TEM, and fluoresce microscopy to study leptin resistance in obese, pregnant, and old mice.
Transcriptome analysis shows that leptin-receptor is not expressed in fenestrated vessels excluding the possibility of receptor-mediated transport. Super-resolution imaging shows leptin transport trough fenestra. Altogether supporting hormonal passive transport through ME fenestra. Electron microscopy (SEM/TEM), provided evidances against the hypothesis that pregnancy affects fenestra densities or induce other structural changes. Therefore, we suggest that leptin resistance might be regulated by other mechanisms. We use similar approachs in aging and obesity.
We also use transgenic perturbations to test VEGF-signaling involvment in ME fenestra maintenance, and wheter these manipulations will affect leptin resistance. Preliminary data showes changes in PLVAP expression levels, under VEGF regulation.
Biophysical properties of fenestra were found critical in liver function. We aim to uncover endothelial role in modulating the hypothalamus ability to sense hormones and control metabolism.