THU124 High Fat Diet Disrupts Blood-Brain Barrier Integrity In Adult Males And Females
Authors: Sheng Julietta A , Handa Robert J , Tobet Stuart A 
Published: October 2023

Disclosure: J.A. Sheng: None. R.J. Handa: None. S.A. Tobet: None.

Background: The blood-brain barrier (BBB) protects the brain from the influx of harmful compounds in the blood. It is comprised of multiple cells, including endothelial cells sharing tight junctions, pericytes, and astrocyte endfeet. The paraventricular nucleus of the hypothalamus (PVN) is 3-5 times more vascularized than surrounding regions in the brain. The current study focuses on the BBB in the PVN as a function of stress. Recent data further suggests a high fat diet (HFD) disrupts the integrity of the BBB and leads to impairment of brain function (Li et al, 2021), suggesting a potential mechanism that may influence stress-related diseases. Methods: Adult male and female mice were placed on standard mouse chow (2918; Tekland) or a HFD (TD.06414, Tekland) for 6 weeks and further divided into control and stressed groups. Control mice were euthanized directly out of their home cage and stressed mice were euthanized 60-min after a 20-min acute restraint stress. Mice were perfused with fluorescein isothiocyanate in phosphate buffered saline followed by fixation with 4% paraformaldehyde to visualize blood vessel integrity (FITC leakage; Frahm & Tobet, 2015). Immunolabeled Glial Fibrillary Acidic Protein (GFAP; astrocytic end feet) and IBA-1 (microglia) were used to further assess BBB integrity and neuroinflammation. Results: Results showed ∼40% more FITC leakage in the PVN vasculature in adult HFD females (p&lt;0.0001) but not males. Similar leakage was not noted in the region lateral to the PVN. IBA-1 immunoreactivity (microglia) showed a HFD-related 50% increase in raw cell counts (p&lt;0.001) and a HFD x restraint decrease in fluorescence intensity (p&lt;0.02) in both sexes. GFAP immunoreactivity (astrocyte end feet) additionally showed 2-fold increase in cell counts in both sexes by HFD (p&lt;0.0001) and a female-specific HFD-induced increase in area (∼40%; p&lt;0.001). Conclusions: Data suggest a chronic high fat diet impairs BBB integrity in PVN vasculature that can be exacerbated further by a brief exposure to stress in adult mice. This effect is being further studied at the cellular level in astrocytes and microglia. Such changes in these BBB components could indicate critical roles for the uniquely dense PVN vasculature, increasing risk of damage to neural functions that could include obesity, cardiovascular autonomic regulation, or depression-like behaviors. Supported by ORWH-NIMH U54 MH118919 SCORE.

References: Li C, Shi L, Wang Y, Peng C, Wu L, Zhang Y, Du Z. (2021). High-fat diet exacerbates lead-induced blood-brain barrier disruption by disrupting tight junction integrity. Environ Toxicol. 36(7):1412-1421. doi: 10.1002/tox.23137.

Frahm KA, Tobet SA. (2015). Development of the blood-brain barrier within the paraventricular nucleus of the hypothalamus: influence of fetal glucocorticoid excess. Brain Struct Funct. 220(4): 2225-2234. doi: 10.1007/s00429-014-0787-8.

Presentation: Thursday, June 15, 2023