Reprogramming of rhythmic liver metabolism by intestinal clock

Area of Science:

• Chronobiology
• Metabolic disease
• Hepatology

Background:

• The local intestinal clock coordinates nutrient processing and absorption.
• Intestinal rhythms may influence peripheral rhythms through diurnal nutritional signals.
• The role of the intestinal clock in controlling liver rhythmicity and metabolism is investigated.

Purpose of the Study:

• To investigate the role of the intestinal clock in controlling liver rhythmicity and metabolism.
• To understand how intestinal clock disruption impacts hepatic diurnal metabolism and rhythmicity.

Main Methods:

• Transcriptomic analysis, metabolomics, metabolic assays, histology, qPCR, and immunoblotting.
• Utilized intestine-specific knockout (iKO) mouse models for Bmal1 and Rev-erba.
• Control mice were used for comparison.

Main Results:

• Intestinal Bmal1 knockout (iKO) reprogrammed the liver transcriptome and impaired clock entrainment.
• Bmal1 iKO shifted hepatic metabolism from lipogenesis to gluconeogenesis, causing hyperglycemia and insulin insensitivity.
• Rev-erba iKO shifted metabolism towards lipogenesis, increasing susceptibility to alcohol-related liver injury.

Conclusions:

• The intestinal clock plays a pivotal role in dictating liver rhythmicity and diurnal metabolism.
• Disruption of the intestinal clock leads to metabolic dysfunction and liver pathologies.
• Targeting intestinal rhythms offers a novel approach for improving metabolic health.