β-Hydroxy-β-methylbutyrate (HMB) increases muscle mass and diminishes weight gain in high-fat-fed mice

β-Hydroxy-β-methylbutyrate (HMB) is a catabolite of leucine, which promotes muscle growth. However, little is known about the effect of HMB on body composition in the context of a high-fat diet. Our aim was to study the circadian metabolic effect of HMB on body weight. C57BL male mice were fed ad libitum chow diet (C), chow diet supplemented with 500 mg Ca-HMB per 1 kg body weight (C+HMB), a high-fat diet (HFD) or HFD supplemented with 500 mg Ca-HMB per 1 kg body weight (HFD+HMB) for 7 weeks. HMB led to reduced fat weight (30%, P<.05) and body weight (7%, P<.05) and increased muscle weight (17%, P<.05) in the HFD+HMB group. HMB increased glucose oxidation (27%, P<.0001) and reduced fatty acid oxidation (30%, P<.0001) in the C group, but increased fatty acid oxidation in the HFD+HMB group (10%, P<.05). At the molecular level, HMB did not affect metabolic proteins in the liver, but lowered NF-κB levels in adipose tissue (24%, P<.05). In the muscle, HMB showed no activation of AKT and mTOR, but did show activation of P70S6K (67%, P<.01) and S6 (42%, P<.01). The activation of the P70S6K and S6 was independent of AKT and mTOR and was accompanied by increased activation of phospholipase D2 (PLD) (35%, P<.0001). In addition, HMB led to altered circadian rhythms. In conclusion, mice fed a HFD supplemented with HMB have increased muscle weight and reduced fat mass and body weight presumably due to increased locomotor activity. HMB induces myogenesis by activating P70S6K and S6 via PLD2.