Cell Reports (Mar 2024)
Iron overload in hypothalamic AgRP neurons contributes to obesity and related metabolic disorders
- 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
Affiliations
- Yi Zhang
- Shanghai 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
- Liwei Chen
- Shanghai 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
- Ye Xuan
- Shanghai 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
- Lina Zhang
- Shanghai 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, China
- Wen Tian
- Shanghai 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, China
- Yangyang Zhu
- Shanghai 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
- Jinghui Wang
- Shanghai 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, China
- Xinyu Wang
- School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China
- Jin Qiu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
- Jian Yu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China
- Mengyang Tang
- Shanghai 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
- Zhen He
- Shanghai 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
- Hong Zhang
- Shanghai 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
- Si Chen
- Shanghai 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
- Yun Shen
- Shanghai 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
- Siyi Wang
- Department of Pathology, Shanghai Sixth People’s Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Rong Zhang
- Shanghai 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
- Lingyan Xu
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China; Corresponding author
- Xinran Ma
- Shanghai 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 author
- Yunfei Liao
- Department of Endocrinology, Wuhan Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China; Corresponding author
- Cheng Hu
- Shanghai 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 author
- Journal volume & issue
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Vol. 43,
no. 3
p. 113900
Abstract
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.
