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Famsin, a novel gut-secreted hormone, contributes to metabolic adaptations to fasting via binding to its receptor OLFR796

Cell Research (2023)Cite this article

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Abstract

The intestine is responsible for nutrient absorption and orchestrates metabolism in different organs during feeding, a process which is partly controlled by intestine-derived hormones. However, it is unclear whether the intestine plays an important role in metabolism during fasting. Here we have identified a novel hormone, famsin, which is secreted from the intestine and promotes metabolic adaptations to fasting. Mechanistically, famsin is shed from a single-pass transmembrane protein, Gm11437, during fasting and then binds OLFR796, an olfactory receptor, to activate intracellular calcium mobilization. This famsin-OLFR796 signaling axis promotes gluconeogenesis and ketogenesis for energy mobilization, and torpor for energy conservation during fasting. In addition, neutralization of famsin by an antibody improves blood glucose profiles in diabetic models, which identifies famsin as a potential therapeutic target for treating diabetes. Therefore, our results demonstrate that communication between the intestine and other organs by a famsin-OLFR796 signaling axis is critical for metabolic adaptations to fasting.

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Fig. 1: Famsin is secreted after cleavage from Gm11437 by furin.
Fig. 2: Famsin is secreted from the intestine and promotes fasting-induced metabolism.
Fig. 3: Famsin promotes torpor and starvation resistance.
Fig. 4: OLFR796 is a receptor of famsin.
Fig. 5: Famsin activates OLFR796-coupled calcium signaling.
Fig. 6: Olfr796 knockout attenuates metabolic adaptations to fasting.
Fig. 7: Neutralization of famsin reduces blood glucose levels in mice.

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Acknowledgements

We thank Drs. Haiteng Deng, Zhongchen Xie, Ye-Guang Chen, Tong-Jin Zhao, Shengcai Lin, Liangyou Rui, Y. Eugene Chen, Cheng Zhan, Jay D. Horton, Wei Shen and all lab members for discussion and technical help. We thank Dr. Isabel Hanson for editing. This work was supported by grants from the National Natural Science Foundation of China (91957206 and 82088102), Tsinghua University Initiative Scientific Research Program (2021Z11JCQ016) and the Ministry of Science and Technology of the People’s Republic of China (2021YFA0804801).

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  1. These authors contributed equally: Aijun Long, Yang Liu.

Authors and Affiliations

  1. State Key Laboratory of Membrane Biology, MOE Key Laboratory of Bioinformatics, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, China

    Aijun Long, Yang Liu, Xinlei Fang, Liangjie Jia, Zhiyuan Li & Yiguo Wang

  2. The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China

    Jiang Hu, Shuang Wu & Ping Huang

  3. The First Clinical Medical College of Zhejiang Chinese Medical University, Hangzhou, Zhejiang, China

    Chao Chen

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Contributions

A.L., Y.L., X.F., L.J. and Z.L. performed the experiments. J.H., S.W., C.C. and P.H. collected the basic parameters from human blood samples. Y.W. conceived, designed and supervised this study, and wrote the manuscript. All authors reviewed and commented on the manuscript.

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Correspondence to Ping Huang or Yiguo Wang.

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Y.W., A.L. and Y.L. have one pending patent application. All other authors declare no competing interests.

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Long, A., Liu, Y., Fang, X. et al. Famsin, a novel gut-secreted hormone, contributes to metabolic adaptations to fasting via binding to its receptor OLFR796. Cell Res (2023). https://doi.org/10.1038/s41422-023-00782-7

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