Volume 35, No 2, Feb 2025

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 35 Issue 2, February 2025: 117-131   |  Open Access

ORIGINAL ARTICLES

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

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 Zheng^1,* , He Huang^1,* , Jin Li^1,*

¹State 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
²Department of Endocrinology, The First Affiliated Hospital and Clinical Medicine College, Henan University of Science and Technology, Luoyang, Henan, China
³National Center for Clinical Research of Metabolic Diseases, Luoyang Center for Endocrinology and Metabolism, Luoyang, Henan, China
⁴Diabetic Nephropathy Academician Workstation of Henan Province, Luoyang, Henan, China
⁵Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, USA
⁶Department 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
⁷Department of Epidemiology and Biostatistics, School of Public Health, Peking University, Beijing, China
Correspondence: Yan Zheng(yan_zheng@fudan.edu.cn)He Huang(he_huang@fudan.edu.cn)Jin Li(li_jin_lifescience@fudan.edu.cn)

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.

https://doi.org/10.1038/s41422-024-01038-8

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