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Dietary cysteine drives body fat loss via FMRFamide signaling in Drosophila and mouse

Tingting Song^1,† , Wusa Qin^1,† , Zeliang Lai^2,† , Haoyu Li^2,† , Daihan Li^2,† , Baojia Wang¹ , Wuquan Deng³ , Tingzhang Wang¹ , Liming Wang^1,4,* , Rui Huang^2,*

¹Institute of Molecular Physiology, Shenzhen Bay Laboratory, Shenzhen, Guangdong, China
²Center for Neurointelligence, School of Medicine, Chongqing University, Chongqing, China
³Department of Endocrinology and Nephrology, Chongqing University Central Hospital, Chongqing Emergency Medical Center, Chongqing, China
⁴Department of General Surgery, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
^†These authors contributed equally: Tingting Song, Wusa Qin, Zeliang Lai, Haoyu Li, Daihan Li
* Correspondence: Liming Wang(lmwang83@szbl.ac.cn)Rui Huang(huangrui85@cqu.edu.cn)

Obesity imposes a global health threat and calls for safe and effective therapeutic options. Here, we found that protein-rich diet significantly reduced body fat storage in fruit flies, which was largely attributed to dietary cysteine intake. Mechanistically, dietary cysteine increased the production of a neuropeptide FMRFamide (FMRFa). Enhanced FMRFa activity simultaneously promoted energy expenditure and suppressed food intake through its cognate receptor (FMRFaR), both contributing to the fat loss effect. In the fat body, FMRFa signaling promoted lipolysis by increasing PKA and lipase activity. In sweet-sensing gustatory neurons, FMRFa signaling suppressed appetitive perception and hence food intake. We also demonstrated that dietary cysteine worked in a similar way in mice via neuropeptide FF (NPFF) signaling, a mammalian RFamide peptide. In addition, dietary cysteine or FMRFa/NPFF administration provided protective effect against metabolic stress in flies and mice without behavioral abnormalities. Therefore, our study reveals a novel target for the development of safe and effective therapies against obesity and related metabolic diseases.

https://doi.org/10.1038/s41422-023-00800-8

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