Hypermetabolic Effects of Dietary Ketones are Independent of Changes in Skeletal Muscle Mitochondrial Respiration

Abstract

Dietary ketone-mediated increases in energy expenditure (EE) have been attributed to increased adipose thermogenesis; however, little is known regarding the contribution of skeletal muscle to the hypermetabolic phenotype. PURPOSE: Determine if dietary ketone esters increase mitochondrial respiration in skeletal muscle. METHODS: Thirty 5-wk old male C57BL/6J mice were placed on an ad libitum high fat diet (HFD) for 10 weeks. Mice were then randomized to one of three groups (n = 10 per group) for an additional 12 weeks: 1) Control (CON, remain on HFD); 2) Ketone Ester (KE, 22% kcal from KE); 3) Pair-fed (PF, pair-fed to KE group). Body composition was measured during the final week of the study by Quantitative Magnetic Resonance (QMR) and EE was examined by indirect calorimetry. Skeletal muscle mitochondrial respiration was measured by high- resolution respirometry in permeabilized muscle fiber bundles. RESULTS: Body weight in the KE group was 27% lower and total adiposity 54% lower than the PF group (p < 0.05 for both) despite comparable energy intake. Differences in body weight and adiposity were attributed to higher resting (REE) and total (TEE) energy expenditure in the KE group (p<0.05). Markers of mitochondrial biogenesis and thermogenesis were increased in brown adipose and a browning phenotype was observed in inguinal white adipose. However, there were no differences in skeletal muscle mitochondrial respiratory capacity between groups. 0.06 CONCLUSIONS: These results provide further support that dietary ketone esters increase brown and white adipose thermogenesis but do not appear to have effects on mitochondrial respiration in skeletal muscle. Supported by: UAB NORC Pilot and Feasibility Award (P30DK056336).