{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:12:40Z","timestamp":1792789960090,"version":"4.5.0"},"reference-count":27,"publisher":"MDPI AG","issue":"17","license":[{"start":{"date-parts":[[2024,8,26]],"date-time":"2024-08-26T00:00:00Z","timestamp":1724630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"NIH-NHLBI","award":["R01HL163775"],"award-info":[{"award-number":["R01HL163775"]}]},{"name":"NIH-NHLBI","award":["R15 HL14884401"],"award-info":[{"award-number":["R15 HL14884401"]}]},{"name":"NIH-NHLBI","award":["#959725"],"award-info":[{"award-number":["#959725"]}]},{"name":"AHA-AIREA","award":["R01HL163775"],"award-info":[{"award-number":["R01HL163775"]}]},{"name":"AHA-AIREA","award":["R15 HL14884401"],"award-info":[{"award-number":["R15 HL14884401"]}]},{"name":"AHA-AIREA","award":["#959725"],"award-info":[{"award-number":["#959725"]}]},{"name":"OCASCR Research","award":["R01HL163775"],"award-info":[{"award-number":["R01HL163775"]}]},{"name":"OCASCR Research","award":["R15 HL14884401"],"award-info":[{"award-number":["R15 HL14884401"]}]},{"name":"OCASCR Research","award":["#959725"],"award-info":[{"award-number":["#959725"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Obesity has been associated with a chronic increase in sympathetic nerve activity, which can lead to hypertension and other cardiovascular diseases. Preliminary studies from our lab found that oxidative stress and neuroinflammation in the brainstem contribute to sympathetic overactivity in high-fat-diet-induced obese mice. However, with glial cells emerging as significant contributors to various physiological processes, their role in causing these changes in obesity remains unknown. In this study, we wanted to determine the role of palmitic acid, a major form of saturated fatty acid in the high-fat diet, in regulating sympathetic outflow. Human brainstem astrocytes (HBAs) were used as a cell culture model since astrocytes are the most abundant glial cells and are more closely associated with the regulation of neurons and, hence, sympathetic nerve activity. In the current study, we hypothesized that palmitic acid-mediated oxidative stress induces senescence and downregulates glutamate reuptake transporters in HBAs. HBAs were treated with palmitic acid (25 \u03bcM for 24 h) in three separate experiments. After the treatment period, the cells were collected for gene expression and protein analysis. Our results showed that palmitic acid treatment led to a significant increase in the mRNA expression of oxidative stress markers (NQO1, SOD2, and CAT), cellular senescence markers (p21 and p53), SASP factors (TNF\u03b1, IL-6, MCP-1, and CXCL10), and a downregulation in the expression of glutamate reuptake transporters (EAAT1 and EAAT2) in the HBAs. Protein levels of Gamma H2AX, p16, and p21 were also significantly upregulated in the treatment group compared to the control. Our results showed that palmitic acid increased oxidative stress, DNA damage, cellular senescence, and SASP factors, and downregulated the expression of glutamate reuptake transporters in HBAs. These findings suggest the possibility of excitotoxicity in the neurons of the brainstem, sympathoexcitation, and increased risk for cardiovascular diseases in obesity.<\/jats:p>","DOI":"10.3390\/nu16172852","type":"journal-article","created":{"date-parts":[[2024,8,26]],"date-time":"2024-08-26T05:16:24Z","timestamp":1724649384000},"page":"2852","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Palmitic Acid Induces Oxidative Stress and Senescence in Human Brainstem Astrocytes, Downregulating Glutamate Reuptake Transporters\u2014Implications for Obesity-Related Sympathoexcitation"],"prefix":"10.3390","volume":"16","author":[{"given":"Mahesh Kumar","family":"Sivasubramanian","sequence":"first","affiliation":[{"name":"Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9156-8608","authenticated-orcid":false,"given":"Raisa","family":"Monteiro","sequence":"additional","affiliation":[{"name":"Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manoj","family":"Jagadeesh","sequence":"additional","affiliation":[{"name":"Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priya","family":"Balasubramanian","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8525-1295","authenticated-orcid":false,"given":"Madhan","family":"Subramanian","sequence":"additional","affiliation":[{"name":"Department of Physiological Sciences, College of Veterinary Medicine, Oklahoma State University, Stillwater, OK 74078, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,8,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2048004016633371","DOI":"10.1177\/2048004016633371","article-title":"A clinical perspective of obesity, metabolic syndrome and cardiovascular disease","volume":"5","author":"Han","year":"2016","journal-title":"JRSM Cardiovasc. 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