2. Academic Validation
  3. A brain-to-gut signal controls intestinal fat absorption

A brain-to-gut signal controls intestinal fat absorption

  • Nature. 2024 Sep 11. doi: 10.1038/s41586-024-07929-5.
Qianqian Lyu # 1 2,  Wenzhi Xue # 1 3,  Ruixin Liu # 1 2,  Qinyun Ma # 1 2,  Vikram Babu Kasaragod # 4,  Shan Sun # 5,  Qian Li 1,  Yanru Chen 1,  Mingyang Yuan 1,  Yuying Yang 1,  Bing Zhang 5,  Aifang Nie 1 2,  Sheng Jia 1,  Chongrong Shen 1,  Po Gao 6,  Weifang Rong 6,  Chenxi Yu 7,  Yufang Bi 1 2,  Chunlei Zhang 8,  Fajun Nan 7,  Guang Ning 1 2,  Zihe Rao 5,  Xiuna Yang 5,  Jiqiu Wang 9 10,  Weiqing Wang 11 12
Affiliations

Affiliations

  • 1 Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China.
  • 2 Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, SJTUSM, Shanghai, China.
  • 3 Clinical Neuroscience Center, Ruijin Hospital Luwan Branch, SJTUSM, Shanghai, China.
  • 4 MRC Laboratory of Molecular Biology, Cambridge, UK.
  • 5 Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, China.
  • 6 Department of Anatomy and Physiology, SJTUSM, Shanghai, China.
  • 7 The Chinese National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
  • 8 Institut Pasteur, Université de Paris, Neural Circuits for Spatial Navigation and Memory, Paris, France.
  • 9 Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China. wangjq@shsmu.edu.cn.
  • 10 Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, SJTUSM, Shanghai, China. wangjq@shsmu.edu.cn.
  • 11 Department of Endocrine and Metabolic Diseases, Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine (SJTUSM), Shanghai, China. wqingw@shsmu.edu.cn.
  • 12 Shanghai National Clinical Research Center for Metabolic Diseases, Key Laboratory for Endocrine and Metabolic Diseases of the National Health Commission of the PR China, Shanghai National Center for Translational Medicine, Ruijin Hospital, SJTUSM, Shanghai, China. wqingw@shsmu.edu.cn.
  • # Contributed equally.
PMID: 39261733 DOI: 10.1038/s41586-024-07929-5
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.

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