@article{cee2115ac7024f8eafe252beb010ba27,
title = "Impact of metabolic disorders on the structural, functional, and immunological integrity of the blood-brain barrier: Therapeutic avenues",
abstract = "Mounting evidence has linked the metabolic disease to neurovascular disorders and cognitive decline. Using a murine model of a high-fat high-sugar diet mimicking obesity-induced type 2 diabetes mellitus (T2DM) in humans, we show that pro-inflammatory mediators and altered immune responses damage the blood-brain barrier (BBB) structure, triggering a proinflammatory metabolic phenotype. We find that disruption to tight junctions and basal lamina due to loss of control in the production of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) causes BBB impairment. Together the disruption to the structural and functional integrity of the BBB results in enhanced transmigration of leukocytes across the BBB that could contribute to an initiation of a neuroinflammatory response through activation of microglia. Using a humanized in vitro model of the BBB and T2DM patient post-mortem brains, we show the translatable applicability of our results. We find a leaky BBB phenotype in T2DM patients can be attributed to a loss of junctional proteins through changes in inflammatory mediators and MMP/TIMP levels, resulting in increased leukocyte extravasation into the brain parenchyma. We further investigated therapeutic avenues to reduce and restore the BBB damage caused by HFHS-feeding. Pharmacological treatment with recombinant annexin A1 (hrANXA1) or reversion from a high-fat high-sugar diet to a control chow diet (dietary intervention), attenuated T2DM development, reduced inflammation, and restored BBB integrity in the animals. Given the rising incidence of diabetes worldwide, understanding metabolic-disease-associated brain microvessel damage is vital and the proposed therapeutic avenues could help alleviate the burden of these diseases.",
keywords = "basal lamina, blood-brain barrier, leukocytes migration, metabolic imbalance, MMPs, neuroinflammation, TYPE-2 DIABETES-MELLITUS, GLYCATION END-PRODUCTS, MATRIX METALLOPROTEINASES, OXIDATIVE STRESS, TISSUE INHIBITOR, MEDITERRANEAN DIET, ENDOTHELIAL-CELLS, ALZHEIMER-DISEASE, LAMININ ISOFORMS, LOW-CARBOHYDRATE",
author = "M.H. Sheikh and M. Errede and A. D'Amati and N.Q. Khan and S. Fanti and R.A. Loiola and S. McArthur and G.S.D. Purvis and C.E. O'Riordan and D. Ferorelli and A. Dell'Erba and J. Kieswich and C. Reutelingsperger and E. Maiorano and M. Yaqoob and C. Thiemermann and A. Baragetti and A.L. Catapano and G.D. Norata and F. Marelli-Berg and D. Virgintino and E. Solito",
note = "Funding Information: We would like to thank the following funding bodies for their support: the British Heart Foundation (Grant/Award number: FS 16/60/32739) to M.H.S.; Ministry of Education‐CAPES, Brazil (Grant number: 7326/2014‐09) to R.A.L.; “Cibo, Microbiota, Salute” by “Vini di Batasiolo S.p.A” AL‐RIC19ABARA_01 to A.B.; “Post‐Doctoral Fellowship 2020” by “Fondazione Umberto Veronesi” 2020‐3318 to A.B.; Fondazione Cariplo 2016‐0852 to G.D.N.; EFSD/Lilly European Diabetes Research Programme 2018 to G.D.N.; Fondazione Telethon GGP19146 to G.D.N.; PRIN 2017K55HLC to G.D.N.; Fondazione Cariplo 2015‐0524 and 2015‐0564 to A.L.C.; H2020 REPROGRAM PHC‐03‐2015/667837‐2 to A.L.C.; Ministero della Salute GR‐2011‐02346974 to A.L.C.; ERA NET ER‐2017‐2364981 to A.L.C.; PRIN 2017H5F943 to A.L.C.; FISM Fondazione Italianana Sclerosi Multipla (Cod. 2014/R/21) to E.S. Funding Information: We would like to thank the following funding bodies for their support: the British Heart Foundation (Grant/Award number: FS 16/60/32739) to M.H.S.; Ministry of Education-CAPES, Brazil (Grant number: 7326/2014-09) to R.A.L.; “Cibo, Microbiota, Salute” by “Vini di Batasiolo S.p.A” AL-RIC19ABARA_01 to A.B.; “Post-Doctoral Fellowship 2020” by “Fondazione Umberto Veronesi” 2020-3318 to A.B.; Fondazione Cariplo 2016-0852 to G.D.N.; EFSD/Lilly European Diabetes Research Programme 2018 to G.D.N.; Fondazione Telethon GGP19146 to G.D.N.; PRIN 2017K55HLC to G.D.N.; Fondazione Cariplo 2015-0524 and 2015-0564 to A.L.C.; H2020 REPROGRAM PHC-03-2015/667837-2 to A.L.C.; Ministero della Salute GR-2011-02346974 to A.L.C.; ERA NET ER-2017-2364981 to A.L.C.; PRIN 2017H5F943 to A.L.C.; FISM Fondazione Italianana Sclerosi Multipla (Cod. 2014/R/21) to E.S. Publisher Copyright: {\textcopyright} 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.",
year = "2022",
month = jan,
day = "1",
doi = "10.1096/fj.202101297R",
language = "English",
volume = "36",
journal = "Faseb Journal",
issn = "0892-6638",
publisher = "FASEB",
number = "1",
}