Neurotensin-neurotensin receptor 2 signaling in adipocytes suppresses food intake through regulating ceramide metabolism

Wei Fu; Yuanting Lai; Kexin Li; Yue Yang; Xiao Guo; Qifan Gong; Xiaofeng Zhou; Liying Zhou; Cenxi Liu; Zhi Zhang; Jisun So; Yufeng Zhang; Lin Huang; Guangxing Lu; Chuanyou Yi; Qichu Wang; Chenyu Fan; Chao Liu; Jiaxing Wang; Haiyi Yu; Yimin Zhao; Tao Huang; Hyun Cheol Roh; Tiemin Liu; Huiru Tang; Jianping Qi; Ming Xu; Yan Zheng; He Huang; Jin Li

doi:10.1038/s41422-024-01038-8

Neurotensin-neurotensin receptor 2 signaling in adipocytes suppresses food intake through regulating ceramide metabolism

Cell Res. 2025 Jan 3. doi: 10.1038/s41422-024-01038-8. Online ahead of print.

Authors

Wei Fu^{1

2

3

4}, Yuanting Lai¹, Kexin Li¹, Yue Yang¹, Xiao Guo¹, Qifan Gong¹, Xiaofeng Zhou¹, Liying Zhou¹, Cenxi Liu¹, Zhi Zhang¹, Jisun So⁵, Yufeng Zhang¹, Lin Huang¹, Guangxing Lu¹, Chuanyou Yi¹, Qichu Wang¹, Chenyu Fan⁶, Chao Liu⁶, Jiaxing Wang⁶, Haiyi Yu⁶, Yimin Zhao⁷, Tao Huang⁷, Hyun Cheol Roh⁵, Tiemin Liu¹, Huiru Tang¹, Jianping Qi¹, Ming Xu⁶, Yan Zheng⁸, He Huang⁹, Jin Li¹⁰

Affiliations

¹ State Key Laboratory of Genetic Engineering, School of Life Sciences, Institute of Metabolism and Integrative Biology, Human Phenome Institute and Zhongshan Hospital, Fudan University, Shanghai, China.
² Department of Endocrinology, The First Affiliated Hospital and Clinical Medicine College, Henan University of Science and Technology, Luoyang, Henan, China.
³ National Center for Clinical Research of Metabolic Diseases, Luoyang Center for Endocrinology and Metabolism, Luoyang, Henan, China.
⁴ Diabetic Nephropathy Academician Workstation of Henan Province, Luoyang, Henan, China.
⁵ Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA.
⁶ Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital; State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University; NHC Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Peking University, Beijing, China.
⁷ Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China.
⁸ State Key Laboratory of Genetic Engineering, School of Life Sciences, Institute of Metabolism and Integrative Biology, Human Phenome Institute and Zhongshan Hospital, Fudan University, Shanghai, China. yan_zheng@fudan.edu.cn.
⁹ State Key Laboratory of Genetic Engineering, School of Life Sciences, Institute of Metabolism and Integrative Biology, Human Phenome Institute and Zhongshan Hospital, Fudan University, Shanghai, China. he_huang@fudan.edu.cn.
¹⁰ State Key Laboratory of Genetic Engineering, School of Life Sciences, Institute of Metabolism and Integrative Biology, Human Phenome Institute and Zhongshan Hospital, Fudan University, Shanghai, China. li_jin_lifescience@fudan.edu.cn.

PMID: 39748047
DOI: 10.1038/s41422-024-01038-8

Abstract

Neurotensin (NTS) is a secretory peptide produced by lymphatic endothelial cells. Our previous study revealed that NTS suppressed the activity of brown adipose tissue via interactions with NTSR2. In the current study, we found that the depletion of Ntsr2 in white adipocytes upregulated food intake, while the local treatment of NTS suppressed food intake. Our mechanistic study revealed that suppression of NTS-NTSR2 signaling enhanced the phosphorylation of ceramide synthetase 2, increased the abundance of its products ceramides C20-C24, and downregulated the production of GDF15 in white adipose tissues, which was responsible for the elevation of food intake. We discovered a potential causal and positive correlation between serum C20-C24 ceramide levels and human food intake in four populations with different ages and ethnic backgrounds. Together, our study shows that NTS-NTSR2 signaling in white adipocytes can regulate food intake via its direct control of lipid metabolism and production of GDF15. The ceramides C20-C24 are key factors regulating food intake in mammals.

Abstract

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