A brain-to-gut signal controls intestinal fat absorption.

Area of Science:

• Neuroscience
• Gastroenterology
• Pharmacology

Background:

• Dietary fat is essential for energy, but excess intake causes obesity.
• Intestinal fat absorption is primarily believed to occur via diffusion.
• The brain-gut axis's role in fat absorption is not well understood.

Purpose of the Study:

• To investigate the role of the dorsal motor nucleus of vagus (DMV) in regulating intestinal fat absorption.
• To identify mechanisms by which the DMV influences fat absorption.
• To explore the therapeutic potential of targeting the DMV-vagus pathway for weight management.

Main Methods:

• Inactivation and activation of DMV neurons in animal models.
• Analysis of jejunal microvilli length and fat absorption.
• Identification and structural analysis of puerarin binding to GABA_A receptors using photoaffinity labeling and cryo-electron microscopy.
• Conditional knockout of Gabra1 in the DMV.

Main Results:

• DMV neuron inactivation reduced intestinal fat absorption and caused weight loss.
• DMV neuron activation increased fat absorption and weight gain.
• Targeting specific DMV neurons projecting to the jejunum shortened microvilli, decreasing fat absorption.
• The natural compound puerarin suppressed the DMV-vagus pathway, reducing fat absorption.
• Puerarin binds to an allosteric site on GABA_A receptors.
• Conditional knockout of Gabra1 in the DMV largely blocked puerarin's effect on fat absorption.

Conclusions:

• The dorsal motor nucleus of vagus (DMV) is a key regulator of intestinal fat absorption via the brain-gut axis.
• Suppression of the DMV-vagus-jejunum axis reduces fat absorption by shortening microvilli.
• Puerarin, acting via GABA_A receptors in the DMV, offers a potential therapeutic strategy for managing fat absorption and promoting weight loss.