Iron overload in hypothalamic AgRP neurons contributes to obesity and related metabolic disorders
Summary: Iron overload is closely associated with metabolic dysfunction. However, the role of iron in the hypothalamus remains unclear. Here, we find that hypothalamic iron levels are increased, particularly in agouti-related peptide (AgRP)-expressing neurons in high-fat-diet-fed mice. Using pharmac...
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| Format: | Article |
| Language: | English |
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Elsevier
2024-03-01
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| Series: | Cell Reports |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124724002286 |
| _version_ | 1827322356748517376 |
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| author | Yi Zhang Liwei Chen Ye Xuan Lina Zhang Wen Tian Yangyang Zhu Jinghui Wang Xinyu Wang Jin Qiu Jian Yu Mengyang Tang Zhen He Hong Zhang Si Chen Yun Shen Siyi Wang Rong Zhang Lingyan Xu Xinran Ma Yunfei Liao Cheng Hu |
| author_facet | Yi Zhang Liwei Chen Ye Xuan Lina Zhang Wen Tian Yangyang Zhu Jinghui Wang Xinyu Wang Jin Qiu Jian Yu Mengyang Tang Zhen He Hong Zhang Si Chen Yun Shen Siyi Wang Rong Zhang Lingyan Xu Xinran Ma Yunfei Liao Cheng Hu |
| author_sort | Yi Zhang |
| collection | DOAJ |
| description | Summary: Iron overload is closely associated with metabolic dysfunction. However, the role of iron in the hypothalamus remains unclear. Here, we find that hypothalamic iron levels are increased, particularly in agouti-related peptide (AgRP)-expressing neurons in high-fat-diet-fed mice. Using pharmacological or genetic approaches, we reduce iron overload in AgRP neurons by central deferoxamine administration or transferrin receptor 1 (Tfrc) deletion, ameliorating diet-induced obesity and related metabolic dysfunction. Conversely, Tfrc-mediated iron overload in AgRP neurons leads to overeating and adiposity. Mechanistically, the reduction of iron overload in AgRP neurons inhibits AgRP neuron activity; improves insulin and leptin sensitivity; and inhibits iron-induced oxidative stress, endoplasmic reticulum stress, nuclear factor κB signaling, and suppression of cytokine signaling 3 expression. These results highlight the critical role of hypothalamic iron in obesity development and suggest targets for treating obesity and related metabolic disorders. |
| first_indexed | 2024-04-25T01:22:04Z |
| format | Article |
| id | doaj.art-113970000ab24969ac0cd5665c0aa046 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-04-25T01:22:04Z |
| publishDate | 2024-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-113970000ab24969ac0cd5665c0aa0462024-03-09T09:24:53ZengElsevierCell Reports2211-12472024-03-01433113900Iron overload in hypothalamic AgRP neurons contributes to obesity and related metabolic disordersYi Zhang0Liwei Chen1Ye Xuan2Lina Zhang3Wen Tian4Yangyang Zhu5Jinghui Wang6Xinyu Wang7Jin Qiu8Jian Yu9Mengyang Tang10Zhen He11Hong Zhang12Si Chen13Yun Shen14Siyi Wang15Rong Zhang16Lingyan Xu17Xinran Ma18Yunfei Liao19Cheng Hu20Shanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, ChinaShanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, ChinaShanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, ChinaShanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; School of Public Health, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, ChinaShanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; Department of Endocrinology, Jinzhou Medical University, Jinzhou 121001, ChinaShanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; Institute for Metabolic Disease, Fengxian Central Hospital Affiliated to Southern Medical University, Shanghai 226001, ChinaShanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; Department of Endocrinology, Xihua Xian People’s Hospital, Zhoukou 466000, ChinaSchool of Life Science and Technology, ShanghaiTech University, Shanghai 201210, ChinaShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, ChinaShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, ChinaShanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; Institute for Metabolic Disease, Fengxian Central Hospital Affiliated to Southern Medical University, Shanghai 226001, ChinaShanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, ChinaShanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, ChinaShanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, ChinaShanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, ChinaDepartment of Pathology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, ChinaShanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, ChinaShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China; Corresponding authorShanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China; Chongqing Institute for Brain and Intelligence, Guangyang Bay Laboratory, Chongqing 400064, China; Corresponding authorDepartment of Endocrinology, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Corresponding authorShanghai Diabetes Institute, Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Clinical Centre for Diabetes, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200233, China; Institute for Metabolic Disease, Fengxian Central Hospital Affiliated to Southern Medical University, Shanghai 226001, China; Corresponding authorSummary: Iron overload is closely associated with metabolic dysfunction. However, the role of iron in the hypothalamus remains unclear. Here, we find that hypothalamic iron levels are increased, particularly in agouti-related peptide (AgRP)-expressing neurons in high-fat-diet-fed mice. Using pharmacological or genetic approaches, we reduce iron overload in AgRP neurons by central deferoxamine administration or transferrin receptor 1 (Tfrc) deletion, ameliorating diet-induced obesity and related metabolic dysfunction. Conversely, Tfrc-mediated iron overload in AgRP neurons leads to overeating and adiposity. Mechanistically, the reduction of iron overload in AgRP neurons inhibits AgRP neuron activity; improves insulin and leptin sensitivity; and inhibits iron-induced oxidative stress, endoplasmic reticulum stress, nuclear factor κB signaling, and suppression of cytokine signaling 3 expression. These results highlight the critical role of hypothalamic iron in obesity development and suggest targets for treating obesity and related metabolic disorders.http://www.sciencedirect.com/science/article/pii/S2211124724002286CP: MetabolismCP: Neuroscience |
| spellingShingle | Yi Zhang Liwei Chen Ye Xuan Lina Zhang Wen Tian Yangyang Zhu Jinghui Wang Xinyu Wang Jin Qiu Jian Yu Mengyang Tang Zhen He Hong Zhang Si Chen Yun Shen Siyi Wang Rong Zhang Lingyan Xu Xinran Ma Yunfei Liao Cheng Hu Iron overload in hypothalamic AgRP neurons contributes to obesity and related metabolic disorders Cell Reports CP: Metabolism CP: Neuroscience |
| title | Iron overload in hypothalamic AgRP neurons contributes to obesity and related metabolic disorders |
| title_full | Iron overload in hypothalamic AgRP neurons contributes to obesity and related metabolic disorders |
| title_fullStr | Iron overload in hypothalamic AgRP neurons contributes to obesity and related metabolic disorders |
| title_full_unstemmed | Iron overload in hypothalamic AgRP neurons contributes to obesity and related metabolic disorders |
| title_short | Iron overload in hypothalamic AgRP neurons contributes to obesity and related metabolic disorders |
| title_sort | iron overload in hypothalamic agrp neurons contributes to obesity and related metabolic disorders |
| topic | CP: Metabolism CP: Neuroscience |
| url | http://www.sciencedirect.com/science/article/pii/S2211124724002286 |
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