Response of Liver Metabolic Pathways to Ketogenic Diet and Exercise Are Not Additive

• Published in: Medicine and science in sports and exercise Vol. 52; no. 1; pp. 37 - 48
• Main Authors: HUANG, TAI-YU, GOLDSMITH, FELICIA R., FULLER, SCOTT E., SIMON, JACOB, BATDORF, HEIDI M., SCOTT, MATTHEW C., ESSAJEE, NABIL M., BROWN, JOHN M., BURK, DAVID H., MORRISON, CHRISTOPHER D., BURKE, SUSAN J., COLLIER, J. JASON, NOLAND, ROBERT C.
• Format: Journal Article
• Language: English
• Published: United States Lippincott Williams & Wilkins 01-01-2020; American College of Sports Medicine
• Subjects: 3-Hydroxybutyric Acid - blood; AMP-Activated Protein Kinases - metabolism; Animals; Basic Sciences; Blood Glucose - metabolism; Diet, Ketogenic; Energy Metabolism; Fatty Acids - metabolism; Ketones - metabolism; Leucine - metabolism; Lipid Metabolism; Liver - metabolism; Liver Glycogen - metabolism; Male; Metabolic Networks and Pathways; Mice, Inbred C57BL; Mitochondrial Dynamics; Oxidation-Reduction; Pancreas - metabolism; Pancreatic Hormones - metabolism; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism; Peroxisomes - metabolism; Physical Conditioning, Animal - physiology; Triglycerides - metabolism
• ISSN: 0195-9131; 1530-0315
• DOI: 10.1249/MSS.0000000000002105

PURPOSEStudies suggest ketogenic diets (KD) produce favorable outcomes (health and exercise performance); however, most rodent studies have used a low-protein KD, which does not reflect the normal- to high-protein KD used by humans. Liver has an important role in ketoadaptation due to its involvement in gluconeogenesis and ketogenesis. This study was designed to test the hypothesis that exercise training (ExTr) while consuming a normal-protein KD (NPKD) would induce additive/synergistic responses in liver metabolic pathways.
METHODSLean, healthy male C57BL/6J mice were fed a low-fat control diet (15.9% kcal protein, 11.9% kcal fat, 72.2% kcal carbohydrate) or carbohydrate-deficient NPKD (16.1% protein, 83.9% kcal fat) for 6 wk. After 3 wk on the diet, half were subjected to 3-wk treadmill ExTr (5 d·wk, 60 min·d, moderate-vigorous intensity). Upon conclusion, metabolic and endocrine outcomes related to substrate metabolism were tested in liver and pancreas.
RESULTSNPKD-fed mice had higher circulating β-hydroxybutyrate and maintained glucose at rest and during exercise. Liver of NPKD-fed mice had lower pyruvate utilization and greater ketogenic potential as evidenced by higher oxidative rates to catabolize lipids (mitochondrial and peroxisomal) and ketogenic amino acids (leucine). ExTr had higher expression of the gluconeogenic gene, Pck1, but lower hepatic glycogen, pyruvate oxidation, incomplete fat oxidation, and total pancreas area. Interaction effects between the NPKD and ExTr were observed for intrahepatic triglycerides, as well as genes involved in gluconeogenesis, ketogenesis, mitochondrial fat oxidation, and peroxisomal markers; however, none were additive/synergistic. Rather, in each instance the interaction effects showed the NPKD and ExTr opposed each other.
CONCLUSIONSAn NPKD and an ExTr independently induce shifts in hepatic metabolic pathways, but changes do not seem to be additive/synergistic in healthy mice.