Deficiency of ER Ca2+ sensor STIM1 in AgRP neurons confers protection against dietary obesity
Zhuo Chen,
Susu Pan,
Kaili Yin,
Yuejin Zhang,
Xiaoman Yuan,
Sihan Wang,
Shujuan Yang,
Qing Shen,
Yizhe Tang,
Juxue Li,
Youjun Wang,
Yisheng Lu,
Guo Zhang
Affiliations
Zhuo Chen
Key Laboratory of Environmental Health, Ministry of Education, Department of Toxicology, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, Hubei, China
Susu Pan
Key Laboratory of Environmental Health, Ministry of Education, Department of Toxicology, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, Hubei, China
Kaili Yin
Key Laboratory of Environmental Health, Ministry of Education, Department of Toxicology, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, Hubei, China
Yuejin Zhang
Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, Hubei, China; Department of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
Xiaoman Yuan
Beijing Key Laboratory of Gene Resource and Molecular Development, Beijing, China; Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China
Sihan Wang
Key Laboratory of Environmental Health, Ministry of Education, Department of Toxicology, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, Hubei, China
Shujuan Yang
Key Laboratory of Environmental Health, Ministry of Education, Department of Toxicology, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, Hubei, China
Qing Shen
Key Laboratory of Environmental Health, Ministry of Education, Department of Toxicology, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, Hubei, China
Yizhe Tang
Department of Neurology, Shenzhen Institute of Translational Medicine, The First Affiliated Hospital of Shenzhen University Health Science Center, Shenzhen Second People’s Hospital, Shenzhen, Guangdong, China
Juxue Li
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, Jiangsu, China; Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, Jiangsu, China
Youjun Wang
Beijing Key Laboratory of Gene Resource and Molecular Development, Beijing, China; Key Laboratory of Cell Proliferation and Regulation Biology, Ministry of Education, Institute of Cell Biology, College of Life Sciences, Beijing Normal University, Beijing, China
Yisheng Lu
Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, Hubei, China; Department of Physiology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Corresponding author
Guo Zhang
Key Laboratory of Environmental Health, Ministry of Education, Department of Toxicology, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China; Institute for Brain Research, Collaborative Innovation Center for Brain Science, Huazhong University of Science and Technology, Wuhan, Hubei, China; Corresponding author
Summary: Store-operated calcium entry (SOCE) is pivotal in maintaining intracellular Ca2+ level and cell function; however, its role in obesity development remains largely unknown. Here, we show that the stromal interaction molecule 1 (Stim1), an endoplasmic reticulum (ER) Ca2+ sensor for SOCE, is critically involved in obesity development. Pharmacological blockade of SOCE in the brain, or disruption of Stim1 in hypothalamic agouti-related peptide (AgRP)-producing neurons (ASKO), significantly ameliorates dietary obesity and its associated metabolic disorders. Conversely, constitutive activation of Stim1 in AgRP neurons leads to an obesity-like phenotype. We show that the blockade of SOCE suppresses general translation in neuronal cells via the 2′,5′-oligoadenylate synthetase 3 (Oas3)-RNase L signaling. While Oas3 overexpression in AgRP neurons protects mice against dietary obesity, deactivation of RNase L in these neurons significantly abolishes the effect of ASKO. These findings highlight an important role of Stim1 and SOCE in the development of obesity.
