A brain-to-gut signal controls intestinal fat absorption

Qianqian Lyu, Wenzhi Xue, Ruixin Liu, Qinyun Ma, Vikram Babu Kasaragod, Shan Sun, Qian Li, Yanru Chen, Mingyang Yuan, Yuying Yang, Bing Zhang, Aifang Nie, Sheng Jia, Chongrong Shen, Po Gao, Weifang Rong, Chenxi Yu, Yufang Bi, Chunlei Zhang, Fajun Nan, Guang Ning, Zihe Rao, Xiuna Yang, Jiqiu Wang () and Weiqing Wang ()
Additional contact information
Qianqian Lyu: Shanghai Jiao Tong University School of Medicine (SJTUSM)
Wenzhi Xue: Shanghai Jiao Tong University School of Medicine (SJTUSM)
Ruixin Liu: Shanghai Jiao Tong University School of Medicine (SJTUSM)
Qinyun Ma: Shanghai Jiao Tong University School of Medicine (SJTUSM)
Vikram Babu Kasaragod: MRC Laboratory of Molecular Biology
Shan Sun: ShanghaiTech University
Qian Li: Shanghai Jiao Tong University School of Medicine (SJTUSM)
Yanru Chen: Shanghai Jiao Tong University School of Medicine (SJTUSM)
Mingyang Yuan: Shanghai Jiao Tong University School of Medicine (SJTUSM)
Yuying Yang: Shanghai Jiao Tong University School of Medicine (SJTUSM)
Bing Zhang: ShanghaiTech University
Aifang Nie: Shanghai Jiao Tong University School of Medicine (SJTUSM)
Sheng Jia: Shanghai Jiao Tong University School of Medicine (SJTUSM)
Chongrong Shen: Shanghai Jiao Tong University School of Medicine (SJTUSM)
Po Gao: SJTUSM
Weifang Rong: SJTUSM
Chenxi Yu: Chinese Academy of Sciences
Yufang Bi: Shanghai Jiao Tong University School of Medicine (SJTUSM)
Chunlei Zhang: Neural Circuits for Spatial Navigation and Memory
Fajun Nan: Chinese Academy of Sciences
Guang Ning: Shanghai Jiao Tong University School of Medicine (SJTUSM)
Zihe Rao: ShanghaiTech University
Xiuna Yang: ShanghaiTech University
Jiqiu Wang: Shanghai Jiao Tong University School of Medicine (SJTUSM)
Weiqing Wang: Shanghai Jiao Tong University School of Medicine (SJTUSM)

Nature, 2024, vol. 634, issue 8035, 936-943

Abstract: Abstract Although fat is a crucial source of energy in diets, excessive intake leads to obesity. Fat absorption in the gut is prevailingly thought to occur organ-autonomously by diffusion1–3. Whether the process is controlled by the brain-to-gut axis, however, remains largely unknown. Here we demonstrate that the dorsal motor nucleus of vagus (DMV) plays a key part in this process. Inactivation of DMV neurons reduces intestinal fat absorption and consequently causes weight loss, whereas activation of the DMV increases fat absorption and weight gain. Notably, the inactivation of a subpopulation of DMV neurons that project to the jejunum shortens the length of microvilli, thereby reducing fat absorption. Moreover, we identify a natural compound, puerarin, that mimics the suppression of the DMV–vagus pathway, which in turn leads to reduced fat absorption. Photoaffinity chemical methods and cryogenic electron microscopy of the structure of a GABAA receptor–puerarin complex reveal that puerarin binds to an allosteric modulatory site. Notably, conditional Gabra1 knockout in the DMV largely abolishes puerarin-induced intestinal fat loss. In summary, we discover that suppression of the DMV–vagus–jejunum axis controls intestinal fat absorption by shortening the length of microvilli and illustrate the therapeutic potential of puerarin binding to GABRA1 in fat loss.

Date: 2024
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DOI: 10.1038/s41586-024-07929-5

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