Ketone body supplementation in keto-adapted mice reveals metabolic adaptations and glycogen-independent exercise capacity.

ABSTRACT: Ketone body supplementation has gained attention for its metabolic effects, but its impact on exercise metabolism remains controversial. We hypothesized that the metabolic response to ketone supplementation differs between keto-adapted and keto-naïve states. In this study, we investigated the effects of β-hydroxybutyrate (BHB) supplementation in keto-adapted mice. Mice were assigned to three groups: control diet (CON), ketogenic diet (KD), or KD with sodium β-hydroxybutyrate supplementation (KD+BHB) for 6 weeks. Chronic BHB supplementation in keto-adapted mice (KD+BHB) further elevated circulating ketone levels compared to KD alone (2.63 ± 0.53 vs. 1.96 ± 0.34 mM, p < 0.05). Despite significantly lower muscle glycogen content, both KD and KD+BHB groups maintained exercise capacity comparable to controls, demonstrating a glycogen-thrifty effect. During exercise, both KD groups showed greater BHB utilization and glucose preservation compared to controls. Gene expression analysis revealed upregulation of fatty acid oxidation-related genes across multiple tissues in KD+BHB mice, with more pronounced effects than KD alone. Additionally, KD+BHB mice showed increased AMPK phosphorylation (p < 0.05 vs. CON) and reduced mTOR activation (p = 0.058 vs. CON) in liver and skeletal muscle, creating a metabolic environment favoring fat utilization. These findings demonstrate that ketone supplementation in keto-adapted status creates a glycogen-thrifty state during exercise, suggesting metabolic context significantly influences responses to exogenous ketones.

SUBMITTER: Ma S 

PROVIDER: S-EPMC12463570 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature