Neuroplastin-55 is a receptor of Manf and protects against diet-induced obesity by promoting adipose browning
Abstract
The browning of white adipose tissue (WAT) enhances thermogenesis and holds great potential in obesity treatment. Membrane receptors have been proven as essential factors during WAT browning. In this study, we found that transmembrane receptor neuroplastin-55 (Np55) was markedly upregulated in the adipose tissue of both obese individuals and mice. Fat-specific Np55 knockout (Np55 FKO ) sensitized mice to high-fat diet-induced obesity and metabolic disorders, which was attributed to impaired energy expenditure and WAT browning. We identified that mesencephalic astrocyte-derived neurotrophic factor (Manf) acts as a ligand for Np55 with high binding affinity. Mechanistically, Np55 forms a complex with tumor necrosis factor receptor associated factor-2 (TRAF2) and apoptosis signal-regulating kinase 1 (ASK1) to activate p38 mitogen-activated protein kinase (MAPK) signaling pathway and conduct WAT browning after Manf stimulation. Additionally, we identified a single-nucleotide polymorphism (rs2470738600) in Manf compromised the binding affinity to Np55 and thermogenic capacity. Finally, we showed that Np55 is indispensable for Manf-induced thermogenesis and weight loss in obese mice. Our results underscore the pivotal role of Np55 as a receptor of Manf in maintaining metabolic homeostasis, highlighting its potential as a therapeutic target for obesity and related disorders.
Article Details
Journal Info
Proceedings of the National Academy of Sciences
National Academy of Sciences
Authors (18)
Qingyi Jia
Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu
Jinhang Zhang
Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu
Haiying Song
Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu
Jiahao Chen
Spin-X Institute, School of Chemistry and Chemical Engineering, School of Biomedical Sciences and Engineering, Guangdong-Hong Kong-Macao Joint Laboratory of Optoelectronic and Magnetic Functional Materials, State Key Laboratory of Luminescent Materials and Devices
Zhenyu Zhang
Huihui Yu
Department of Endocrinology and Metabolism, West China Hospital, Sichuan University, Chengdu
Yi Chen
Qinhui Liu
Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu
Xiandan Jing
Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu
Haixia Xu
Jingwei Li
Process Research and Development
Yimin Xiong
Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu
Meilin Ma
Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu
Na Yang
School of Materials and Energy
Junyan Li
Department of Materials Science and Engineering
Yining Xu
Department of Pharmacy, Institute of Metabolic Diseases and Pharmacotherapy, West China Hospital, Sichuan University, Chengdu
Yanping Li
Jinhan He