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Structure paper

TitleA brain-to-gut signal controls intestinal fat absorption.
Journal, issue, pagesNature, Year 2024
Publish dateSep 11, 2024
AuthorsQianqian 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 / Weiqing Wang /
PubMed AbstractAlthough 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 diffusion. Whether the ...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 diffusion. 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 GABA 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.
External linksNature / PubMed:39261733
MethodsEM (single particle)
Resolution2.4 Å
Structure data

19907

9eqg

EMDB-19907, PDB-9eqg:
CryoEM structure of human full-length alpha1beta3gamma2L GABA(A)R in complex with GABA and puerarin
Method: EM (single particle) / Resolution: 2.4 Å

Chemicals

ChemComp-PGW:
(1R)-2-{[(S)-{[(2S)-2,3-dihydroxypropyl]oxy}(hydroxy)phosphoryl]oxy}-1-[(hexadecanoyloxy)methyl]ethyl / phospholipid*YM

ChemComp-D10:
DECANE

ChemComp-HEX:
HEXANE

ChemComp-PT5:
[(2R)-1-octadecanoyloxy-3-[oxidanyl-[(1R,2R,3S,4R,5R,6S)-2,3,6-tris(oxidanyl)-4,5-diphosphonooxy-cyclohexyl]oxy-phospho / phospholipid*YM

ChemComp-R16:
HEXADECANE

ChemComp-PLM:
PALMITIC ACID

ChemComp-CL:
Unknown entry

ChemComp-ABU:
GAMMA-AMINO-BUTANOIC ACID

ChemComp-NAG:
2-acetamido-2-deoxy-beta-D-glucopyranose


PDB Unreleased entry

PDB-1h6w: Unknown entry

ChemComp-PX2:
1,2-DILAUROYL-SN-GLYCERO-3-PHOSPHATE

ChemComp-HOH:
WATER

Source
  • homo sapiens (human)
KeywordsMEMBRANE PROTEIN / GABA(A) receptor / Inhibitory synapse / GABA / Puerarin / Fat regulation

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