β-Hydroxybutyrate Modulates Metabolic Signaling and Partially Restores Peripheral Circadian Rhythms in High-Fat Diet-Fed Mice

May 4, 2026Foods (Basel, Switzerland)

Beta-Hydroxybutyrate Changes Metabolic Signals and Partly Restores Body Clock Rhythms in Mice on a High-Fat Diet

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Abstract

BHB supplementation significantly decreased food intake in HF-fed mice (< 0.01).

A high-fat diet disrupted metabolic homeostasis, leading to increased body weight and adiposity (< 0.01).
The high-fat diet reduced activation of a key metabolic regulator (AMPK) and enhanced signaling pathways associated with growth and inflammation (AKT/mTOR and NF-κB).
BHB supplementation partially reversed molecular alterations in skeletal muscle and adipose tissue by increasing AMPK activation and decreasing mTOR and NF-κB signaling (< 0.05).
BHB appeared to modulate circadian gene expression, particularly restoring rhythmic patterns in adipose tissue.
These findings suggest that BHB may influence nutrient-sensing pathways and restore peripheral circadian rhythms under high-fat dietary conditions.

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A high-fat (HF) diet disrupts metabolic homeostasis and impairs peripheral circadian rhythms in key metabolic tissues. β-Hydroxybutyrate (BHB), a major circulating ketone body, functions not only as an energy substrate but also as a signaling metabolite regulating nutrient-sensing and inflammatory pathways. However, its role in modulating metabolic-circadian interactions under conditions of nutrient excess remains unclear. In this study, we investigated whether BHB supplementation influences metabolic signaling and circadian clock oscillations in liver, skeletal muscle and adipose tissue under chow and HF conditions. Male C57BL/6 mice were fed chow or HF with or without BHB supplementation (500 mg/kg body weight in the diet) for 7 weeks. Metabolic parameters were assessed by indirect calorimetry, and tissues were collected every 4 h across the circadian cycle. HF feeding increased body weight and adiposity (< 0.01), reduced AMPK activation, enhanced AKT/mTOR signaling, elevated NF-κB levels and dampened clock gene rhythmicity. BHB supplementation significantly decreased food intake in HF-fed mice (< 0.01) and partially reversed several molecular alterations in a tissue-specific manner. In skeletal muscle and adipose tissue, BHB increased AMPK activation and reduced mTOR and NF-κB signaling (< 0.05), whereas hepatic effects were more modest. Notably, BHB modulated circadian gene expression, restoring aspects of rhythmic amplitude and/or phase, particularly in adipose tissue. These findings may indicate that BHB supplementation modulates nutrient-sensing pathways and partially restores peripheral circadian rhythms under HF conditions. While some effects may be influenced by reduced energy intake, BHB may serve as a metabolic signal linking nutrient status to circadian regulation. p p p

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β-Hydroxybutyrate Modulates Metabolic Signaling and Partially Restores Peripheral Circadian Rhythms in High-Fat Diet-Fed Mice

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