Hepatic ketogenesis is not required for exercise training to mitigate diet-induced liver steatosis in male mice

Accelerated hepatic fatty acid oxidation during acute exercise has been proposed as a contributor to the antisteatotic effects of exercise training. Ketogenesis, which produces acetoacetate (AcAc) and β-hydroxybutyrate (βOHB) from fatty acids, is stimulated by exercise and supports fat oxidation. This study tested the hypothesis that hepatic ketogenesis is necessary for exercise training to lower liver lipids. Liver-specific 3-hydroxymethylglutaryl-CoA synthase 2 knockout (HMGCS2 KO) mice and wild-type (WT) littermates underwent sedentary, acute exercise (treadmill running), and exercise training (6-wk treadmill running regime) protocols. Liver ketone bodies and lipids were determined via mass spectrometry. Stable isotope infusions in conscious, unrestrained mice defined mitochondrial oxidative fluxes during rest and treadmill running. In untrained mice, hepatic HMGCS2 deletion lowered liver AcAc and βOHB and impaired their increase during acute exercise. Liver triacylglycerides (TAGs) were comparable between genotypes at rest (ad libitum fed and short-fasted conditions). In contrast, liver TAGs were higher in HMGCS2 KO compared with WT mice following acute, nonexhaustive exercise. Acute exercise stimulated TCA cycle flux in both genotypes; however, liver TCA cycle flux was higher in KO mice during rest and acute exercise. This suggests that enhanced lipid oxidation via the TCA cycle may be sufficient for TAG homeostasis in HMGCS2 KO mice at rest, but not during acute exercise. Exercise training decreased liver TAGs similarly in WT and KO mice when assessed under short-fasted conditions. In conclusion, hepatic ketogenesis supports liver lipid homeostasis during acute exercise, but is not required for exercise training to mitigate diet-induced fatty liver.NEW & NOTEWORTHY Exercise training has been proposed to mitigate liver steatosis partly through enhanced hepatic fat oxidation. During acute exercise, the oxidation of fatty acids to ketone bodies is stimulated. This study tested the hypothesis that hepatic ketogenesis was required for exercise training to reduce liver fat in mice. The results show that hepatic ketogenesis supports lipid homeostasis during acute exercise, but is not necessary for exercise training to mitigate diet-induced fatty liver.