{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,12]],"date-time":"2026-09-12T18:44:28Z","timestamp":1789238668623,"version":"build-2803163510"},"reference-count":48,"publisher":"The Endocrine Society","issue":"8","funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["NIHAG059088"],"award-info":[{"award-number":["NIHAG059088"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000738","name":"Veterans Affairs","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100000738","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,6,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>High-fat diet (HFD) consumption increases the risk of metabolic syndrome as manifested by insulin resistance, fatty liver, hypertriglyceridemia, and diabetes mellitus type 2. Blood-brain barrier (BBB) disruptions and impaired BBB transport of metabolic hormones, including leptin, insulin, and ghrelin, occur in diabetes mellitus type 2 and contribute to metabolic dysregulation and cognitive impairment. However, it is unclear whether the BBB changes are caused by the HFD, obesity, insulin resistance, elevated glucose or triglyceride levels, or other aspects of the metabolic syndrome. This study examined the effects of chronic HFD and an early stage of metabolic syndrome on BBB disruption and transport of insulin, leptin, and ghrelin. Mice on the HFD demonstrated obesity, increases in insulin, leptin, plasminogen activator inhibitor-1, and resistin, fatty liver and hyperglycerolemia, without elevations in glucose, triglycerides, ghrelin, glucagon, gastric inhibitory polypeptide, or glucagon-like peptide. The vascular markers of sucrose and albumin did not show BBB disruption. HFD did not alter the rate of insulin, leptin, or ghrelin transport across the BBB. However, leptin binding to the luminal surface of the BBB was greater in the hypothalamus and reduced for the rest of the brain with HFD treatment. The liver uptake of insulin, leptin, and ghrelin was reduced in the HFD group. Overall, our findings indicate that chronic HFD consumption with concomitant obesity and insulin resistance in the absence of hyperglycemia does not result in BBB disruption or altered BBB permeability to key metabolic hormones but may selectively affect vascular binding of important metabolic hormones in the brain and liver.<\/jats:p>","DOI":"10.1210\/endocr\/bqaf095","type":"journal-article","created":{"date-parts":[[2025,5,26]],"date-time":"2025-05-26T16:57:46Z","timestamp":1748278666000},"source":"Crossref","is-referenced-by-count":3,"title":["Blood-Brain Barrier Integrity and Transport of Major Hormones are Unchanged in Mice With Euglycemic Hyperinsulinemia"],"prefix":"10.1210","volume":"166","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8703-9749","authenticated-orcid":false,"given":"Anzela","family":"Niraula","sequence":"first","affiliation":[{"name":"Neuroscience Program, Department of Psychological and Brain Sciences, Colgate University , Hamilton, NY 13346 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kim","family":"Hansen","sequence":"additional","affiliation":[{"name":"Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System , Seattle, WA 98108 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristin M","family":"Bullock","sequence":"additional","affiliation":[{"name":"Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System , Seattle, WA 98108 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2575-1594","authenticated-orcid":false,"given":"Michelle A","family":"Erickson","sequence":"additional","affiliation":[{"name":"Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System , Seattle, WA 98108 ,","place":["USA"]},{"name":"Department of Medicine, University of Washington , Seattle, WA 98195 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0496-3619","authenticated-orcid":false,"given":"William A","family":"Banks","sequence":"additional","affiliation":[{"name":"Geriatric Research Education and Clinical Center, Veterans Affairs Puget Sound Health Care System , Seattle, WA 98108 ,","place":["USA"]},{"name":"Department of Medicine, University of Washington , Seattle, WA 98195 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"80","published-online":{"date-parts":[[2025,5,26]]},"reference":[{"issue":"4","key":"2025061003165507200_bqaf095-B1","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1208\/s12248-017-0079-3","article-title":"Blood-brain barriers in obesity","volume":"19","author":"Rhea","year":"2017","journal-title":"AAPS J"},{"issue":"5","key":"2025061003165507200_bqaf095-B2","doi-asserted-by":"crossref","first-page":"648","DOI":"10.1002\/ana.23648","article-title":"The blood-brain barrier in health and disease","volume":"72","author":"Daneman","year":"2012","journal-title":"Ann Neurol"},{"issue":"11","key":"2025061003165507200_bqaf095-B3","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1161\/CIRCRESAHA.116.308999","article-title":"Obesity, diabetes, and cardiovascular diseases: a compendium","volume":"118","author":"Scherer","year":"2016","journal-title":"Circ Res"},{"issue":"5","key":"2025061003165507200_bqaf095-B4","doi-asserted-by":"crossref","first-page":"1037","DOI":"10.1016\/j.bbadis.2016.04.017","article-title":"Common neurodegenerative pathways in obesity, diabetes, and Alzheimer\u2019s disease","volume":"1863","author":"Pugazhenthi","year":"2017","journal-title":"Biochim Biophys Acta Mol Basis Dis"},{"issue":"8","key":"2025061003165507200_bqaf095-B5","doi-asserted-by":"crossref","first-page":"444","DOI":"10.1038\/s41574-019-0213-7","article-title":"The blood-brain barrier as an endocrine tissue","volume":"15","author":"Banks","year":"2019","journal-title":"Nat Rev Endocrinol"},{"issue":"4","key":"2025061003165507200_bqaf095-B6","doi-asserted-by":"crossref","first-page":"e12929","DOI":"10.1111\/jne.12929","article-title":"A historical perspective on the interactions of insulin at the blood-brain barrier","volume":"33","author":"Rhea","year":"2021","journal-title":"J Neuroendocrinol"},{"issue":"1","key":"2025061003165507200_bqaf095-B7","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1186\/s12974-024-03104-9","article-title":"Obesity-induced blood-brain barrier dysfunction: phenotypes and mechanisms","volume":"21","author":"Feng","year":"2024","journal-title":"J Neuroinflammation"},{"issue":"1","key":"2025061003165507200_bqaf095-B8","doi-asserted-by":"crossref","first-page":"8","DOI":"10.1038\/jcbfm.1983.2","article-title":"Transport of alpha-aminoisobutyric acid across brain capillary and cellular membranes","volume":"3","author":"Blasberg","year":"1983","journal-title":"J Cereb Blood Flow Metab"},{"issue":"1","key":"2025061003165507200_bqaf095-B9","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/jcbfm.1983.1","article-title":"Graphical evaluation of blood-to-brain transfer constants from multiple-time uptake data","volume":"3","author":"Patlak","year":"1983","journal-title":"J Cereb Blood Flow Metab"},{"key":"2025061003165507200_bqaf095-B10","doi-asserted-by":"crossref","unstructured":"Niraula A, Hansen K, Bullock K, Erickson M, Banks WA. Supplemental figure associated with the manuscript, Blood-brain barrier integrity and transport of major hormones are unchanged in mice with euglycemic hyperinsulinemia. figshare. April 2025.","DOI":"10.1210\/endocr\/bqaf095"},{"issue":"21","key":"2025061003165507200_bqaf095-B11","doi-asserted-by":"crossref","first-page":"4179","DOI":"10.1523\/JNEUROSCI.2506-18.2019","article-title":"Endothelial adora2a activation promotes blood-brain barrier breakdown and cognitive impairment in mice with diet-induced insulin resistance","volume":"39","author":"Yamamoto","year":"2019","journal-title":"J Neurosci"},{"issue":"8","key":"2025061003165507200_bqaf095-B12","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1080\/1028415X.2017.1418727","article-title":"One-week exposure to a free-choice high-fat high-sugar diet does not disrupt blood-brain barrier permeability in fed or overnight fasted rats","volume":"22","author":"Rijnsburger","year":"2019","journal-title":"Nutr Neurosci"},{"issue":"5","key":"2025061003165507200_bqaf095-B13","doi-asserted-by":"crossref","first-page":"e12818","DOI":"10.1111\/acel.12818","article-title":"High-fat diet protects the blood-brain barrier in an Alzheimer\u2019s disease mouse model","volume":"17","author":"Elhaik Goldman","year":"2018","journal-title":"Aging Cell"},{"issue":"1","key":"2025061003165507200_bqaf095-B14","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1186\/s12987-023-00478-5","article-title":"Blood-brain borders: a proposal to address limitations of historical blood-brain barrier terminology","volume":"21","author":"Badaut","year":"2024","journal-title":"Fluids Barriers CNS"},{"issue":"4","key":"2025061003165507200_bqaf095-B15","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1016\/j.cmet.2019.08.005","article-title":"Partial leptin reduction as an insulin sensitization and weight loss strategy","volume":"30","author":"Zhao","year":"2019","journal-title":"Cell Metab"},{"issue":"7121","key":"2025061003165507200_bqaf095-B16","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1038\/nature05482","article-title":"Mechanisms linking obesity to insulin resistance and type 2 diabetes","volume":"444","author":"Kahn","year":"2006","journal-title":"Nature"},{"issue":"9","key":"2025061003165507200_bqaf095-B17","doi-asserted-by":"crossref","first-page":"2369","DOI":"10.2337\/dc07-0649","article-title":"Insulin resistance syndrome in the elderly","volume":"30","author":"Banks","year":"2007","journal-title":"Diabetes Care"},{"issue":"2","key":"2025061003165507200_bqaf095-B18","doi-asserted-by":"crossref","first-page":"147","DOI":"10.1159\/000381224","article-title":"Fatty acids, obesity and insulin resistance","volume":"8","author":"Arner","year":"2015","journal-title":"Obes Facts"},{"issue":"11","key":"2025061003165507200_bqaf095-B19","doi-asserted-by":"crossref","first-page":"3732","DOI":"10.2337\/dc13-0800","article-title":"Glycerol and fatty acids in serum predict the development of hyperglycemia and type 2 diabetes in Finnish men","volume":"36","author":"Mahendran","year":"2013","journal-title":"Diabetes Care"},{"issue":"1","key":"2025061003165507200_bqaf095-B20","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/j.mce.2011.02.009","article-title":"Ghrelin in type 2 diabetes mellitus and metabolic syndrome","volume":"340","author":"Ukkola","year":"2011","journal-title":"Mol Cell Endocrinol"},{"issue":"11","key":"2025061003165507200_bqaf095-B21","doi-asserted-by":"crossref","first-page":"1691","DOI":"10.1016\/0026-0495(78)90291-3","article-title":"Role of glucagon in the pathogenesis of diabetes: the status of the controversy","volume":"27","author":"Unger","year":"1978","journal-title":"Metabolism"},{"issue":"2","key":"2025061003165507200_bqaf095-B22","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1152\/physrev.00013.2014","article-title":"Physiology of proglucagon peptides: role of glucagon and glp-1 in health and disease","volume":"95","author":"Sandoval","year":"2015","journal-title":"Physiol Rev"},{"issue":"6","key":"2025061003165507200_bqaf095-B23","first-page":"H2660","article-title":"Streptozotocin-induced diabetes progressively increases blood-brain barrier permeability in specific brain regions in rats","volume":"291","author":"Huber","year":"2006","journal-title":"Am J Physiol"},{"issue":"1","key":"2025061003165507200_bqaf095-B24","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1210\/en.2011-1638","article-title":"Topiramate treatment protects blood-brain barrier pericytes from hyperglycemia-induced oxidative damage in diabetic mice","volume":"153","author":"Price","year":"2012","journal-title":"Endocrinology"},{"issue":"3","key":"2025061003165507200_bqaf095-B25","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1124\/jpet.116.237057","article-title":"Blood-brain barrier disruption and neurovascular unit dysfunction in diabetic mice: protection with the mitochondrial carbonic anhydrase inhibitor topiramate","volume":"359","author":"Salameh","year":"2016","journal-title":"J Pharmacol Exp Therap"},{"issue":"1","key":"2025061003165507200_bqaf095-B26","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12987-018-0121-6","article-title":"Disruption of the hippocampal and hypothalamic blood-brain barrier in a diet-induced obese model of type ii diabetes: prevention and treatment by the mitochondrial carbonic anhydrase inhibitor, topiramate","volume":"16","author":"Salameh","year":"2019","journal-title":"Fluids Barriers CNS"},{"issue":"9","key":"2025061003165507200_bqaf095-B27","doi-asserted-by":"crossref","first-page":"1525","DOI":"10.2337\/diabetes.49.9.1525","article-title":"Obesity induced by a high-fat diet is associated with reduced brain insulin transport in dogs","volume":"49","author":"Kaiyala","year":"2000","journal-title":"Diabetes"},{"issue":"7","key":"2025061003165507200_bqaf095-B28","doi-asserted-by":"crossref","first-page":"3592","DOI":"10.1210\/en.2008-0008","article-title":"Starvation and triglycerides reverse the obesity-induced impairment of insulin transport at the blood-brain barrier","volume":"149","author":"Urayama","year":"2008","journal-title":"Endocrinology"},{"issue":"7","key":"2025061003165507200_bqaf095-B29","doi-asserted-by":"crossref","first-page":"627","DOI":"10.1016\/0024-3205(85)90166-3","article-title":"Genetically obese zucker rats have abnormally low brain insulin content","volume":"36","author":"Baskin","year":"1985","journal-title":"Life Sci"},{"issue":"suppl_3","key":"2025061003165507200_bqaf095-B30","doi-asserted-by":"crossref","first-page":"S215","DOI":"10.2337\/diabetes.53.suppl_3.S215","article-title":"The high-fat diet-fed mouse: a model for studying mechanisms and treatment of impaired glucose tolerance and type 2 diabetes","volume":"53","author":"Winzell","year":"2004","journal-title":"Diabetes"},{"issue":"5487","key":"2025061003165507200_bqaf095-B31","doi-asserted-by":"crossref","first-page":"2122","DOI":"10.1126\/science.289.5487.2122","article-title":"Role of brain insulin receptor in control of body weight and reproduction","volume":"289","author":"Bruning","year":"2000","journal-title":"Science (Washington DC)"},{"issue":"1","key":"2025061003165507200_bqaf095-B32","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1186\/s12987-023-00431-6","article-title":"Central nervous system insulin signaling can influence the rate of insulin influx into brain","volume":"20","author":"Nguyen","year":"2023","journal-title":"Fluids Barriers CNS"},{"issue":"1","key":"2025061003165507200_bqaf095-B33","doi-asserted-by":"crossref","first-page":"e174595","DOI":"10.1172\/JCI174595","article-title":"Leptin physiology and pathophysiology: knowns and unknowns 30 years after its discovery","volume":"134","author":"Flier","year":"2024","journal-title":"J Clin Invest"},{"issue":"12","key":"2025061003165507200_bqaf095-B34","doi-asserted-by":"crossref","first-page":"1827","DOI":"10.1172\/JCI9842","article-title":"Two defects contribute to hypothalamic leptin resistance in mice with diet-induced obestiy","volume":"105","author":"El Haschimi","year":"2000","journal-title":"J Clin Invest"},{"issue":"16","key":"2025061003165507200_bqaf095-B35","doi-asserted-by":"crossref","first-page":"8878","DOI":"10.1073\/pnas.94.16.8878","article-title":"Physiological response to long-term peripheral and central leptin infusion in lean and obese mice","volume":"94","author":"Halaas","year":"1997","journal-title":"Proc Natl Acad Sci U S A"},{"issue":"11","key":"2025061003165507200_bqaf095-B36","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.1016\/S0196-9781(99)00139-4","article-title":"Impaired transport of leptin across the blood-brain barrier in obesity","volume":"20","author":"Banks","year":"1999","journal-title":"Peptides"},{"issue":"1","key":"2025061003165507200_bqaf095-B37","doi-asserted-by":"crossref","first-page":"R143","DOI":"10.1152\/ajplegacy.1944.141.1.143","article-title":"Obesity-prone rats have normal blood-brain barrier transport but defective central leptin signaling before obesity onset","volume":"286","author":"Levin","year":"2004","journal-title":"Am J Physiol"},{"issue":"4","key":"2025061003165507200_bqaf095-B38","doi-asserted-by":"crossref","first-page":"2351","DOI":"10.1002\/j.2040-4603.2021.tb00183.x","article-title":"Leptin and the blood-brain barrier: curiosities and controversies","volume":"11","author":"Banks","year":"2021","journal-title":"Compr Physiol"},{"issue":"5","key":"2025061003165507200_bqaf095-B39","doi-asserted-by":"crossref","first-page":"1253","DOI":"10.2337\/diabetes.53.5.1253","article-title":"Triglycerides induce leptin resistance at the blood-brain barrier","volume":"53","author":"Banks","year":"2004","journal-title":"Diabetes"},{"issue":"3","key":"2025061003165507200_bqaf095-B40","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1038\/ijo.2017.231","article-title":"Triglycerides cross the blood-brain barrier and induce central leptin and insulin receptor resistance","volume":"42","author":"Banks","year":"2018","journal-title":"Int J Obes"},{"issue":"19","key":"2025061003165507200_bqaf095-B41","doi-asserted-by":"crossref","first-page":"4753","DOI":"10.1113\/JP276149","article-title":"Insulin transport across the blood-brain barrier can occur independently of the insulin receptor","volume":"596","author":"Rhea","year":"2018","journal-title":"J Physiol"},{"key":"2025061003165507200_bqaf095-B42","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.molmet.2018.09.007","article-title":"Ghrelin transport across the blood-brain barrier can occur independently of the growth hormone secretagogue receptor","volume":"18","author":"Rhea","year":"2018","journal-title":"Mol Metab"},{"issue":"11","key":"2025061003165507200_bqaf095-B43","doi-asserted-by":"crossref","first-page":"2061","DOI":"10.1016\/j.peptides.2008.07.001","article-title":"Effects of triglycerides, obesity, and starvation on ghrelin transport across the blood-brain barrier","volume":"29","author":"Banks","year":"2008","journal-title":"Peptides"},{"issue":"5","key":"2025061003165507200_bqaf095-B44","doi-asserted-by":"crossref","first-page":"e0128274","DOI":"10.1371\/journal.pone.0128274","article-title":"High-fat diet induces hepatic insulin resistance and impairment of synaptic plasticity","volume":"10","author":"Liu","year":"2015","journal-title":"PLoS One"},{"issue":"6","key":"2025061003165507200_bqaf095-B45","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.1002\/hep.32589","article-title":"Par2 promotes impaired glucose uptake and insulin resistance in nafld through glut2 and akt interference","volume":"76","author":"Shearer","year":"2022","journal-title":"Hepatology"},{"key":"2025061003165507200_bqaf095-B46","first-page":"189","article-title":"Effect of alloxan diabetes and phenformin on insulin binding with liver plasma membrane receptors","volume":"54","author":"Chaujar","year":"1984","journal-title":"Jpn J Exp Med"},{"issue":"12","key":"2025061003165507200_bqaf095-B47","doi-asserted-by":"crossref","first-page":"3032","DOI":"10.2337\/db10-0074","article-title":"Disruption of hepatic leptin signaling protects mice from age- and diet-related glucose intolerance","volume":"59","author":"Huynh","year":"2010","journal-title":"Diabetes"},{"issue":"36","key":"2025061003165507200_bqaf095-B48","doi-asserted-by":"crossref","first-page":"13163","DOI":"10.1073\/pnas.1411571111","article-title":"Ghrelin promotes hepatic lipogenesis by activation of mtor-ppar\u03b3 signaling pathway","volume":"111","author":"Li","year":"2014","journal-title":"Proc Natl Acad Sci U S A"}],"container-title":["Endocrinology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/endo\/advance-article-pdf\/doi\/10.1210\/endocr\/bqaf095\/63356751\/bqaf095.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/endo\/article-pdf\/166\/8\/bqaf095\/63356751\/bqaf095.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/endo\/article-pdf\/166\/8\/bqaf095\/63356751\/bqaf095.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,6,10]],"date-time":"2025-06-10T07:17:11Z","timestamp":1749539831000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/endo\/article\/doi\/10.1210\/endocr\/bqaf095\/8149298"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,26]]},"references-count":48,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2025,6,10]]}},"URL":"https:\/\/doi.org\/10.1210\/endocr\/bqaf095","relation":{},"ISSN":["1945-7170"],"issn-type":[{"value":"1945-7170","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2025,8]]},"published":{"date-parts":[[2025,5,26]]},"article-number":"bqaf095"}}