β-Hydroxybutyrate Modulates Metabolic Signaling and Partially Restores Peripheral Circadian Rhythms in High-Fat...

Area of Science:

• Metabolic Research
• Circadian Biology
• Nutritional Science

Background:

• High-fat (HF) diets disrupt metabolic homeostasis and peripheral circadian rhythms.
• Beta-hydroxybutyrate (BHB) is a ketone body with signaling roles, but its impact on metabolic-circadian interactions under nutrient excess is unknown.

Purpose of the Study:

• To investigate BHB supplementation's effects on metabolic signaling and circadian clock oscillations in liver, skeletal muscle, and adipose tissue under normal and HF conditions.

Main Methods:

• Male C57BL/6 mice were fed chow or HF diets with or without BHB for 7 weeks.
• Metabolic parameters were assessed using indirect calorimetry.
• Tissue samples were collected every 4 hours across the circadian cycle for molecular analysis.

Main Results:

• HF feeding increased body weight, adiposity, AKT/mTOR signaling, and NF-κB levels, while reducing AMPK activation and dampening clock gene rhythmicity.
• BHB supplementation decreased food intake in HF-fed mice and partially reversed molecular alterations in a tissue-specific manner.
• BHB increased AMPK activation and reduced mTOR and NF-κB signaling in skeletal muscle and adipose tissue, with more modest hepatic effects. BHB also restored aspects of circadian gene expression rhythmicity, particularly in adipose tissue.

Conclusions:

• BHB supplementation modulates nutrient-sensing pathways and partially restores peripheral circadian rhythms in mice fed a high-fat diet.
• BHB may act as a metabolic signal connecting nutrient status to circadian regulation, with effects potentially influenced by reduced energy intake.