Ketogenic diet in combination with voluntary exercise impacts markers of hepatic metabolism and oxidative stress in male and female Wistar rats.

Ketogenic diets (KDs) are shown to benefit hepatic metabolism; however, their effect on the liver when combined with exercise is unknown. We investigated the effects of a KD versus a "western" diet (WD) on markers of hepatic lipid metabolism and oxidative stress in exercising rats. Male and female Wistar rats with access to voluntary running wheels were randomized to 3 groups ( n = 8-14 per group): standard chow (SC; 17% fat), WD (42% fat), or KD (90.5% fat) for 7 weeks. Body fat percentage (BF%) was increased in WD and KD versus SC, although KD females displayed lower BF% versus WD ( p ≤ 0.05). Liver triglycerides were higher in KD and WD versus SC but were attenuated in KD females versus WD ( p ≤ 0.05). KD suppressed hepatic markers of de novo lipogenesis (fatty acid synthase, acetyl coenzyme A carboxylase) and increased markers of mitochondrial biogenesis/content (peroxisome proliferator activated receptor-1α, mitochondrial transcription factor A (TFAM), and citrate synthase activity). KD also increased hepatic glutathione peroxidase 1 and lowered oxidized glutathione. Female rats exhibited elevated hepatic markers of mitochondrial biogenesis (TFAM), mitophagy (light chain 3 II/I ratio, autophagy-related protein 12:5), and cellular energy homeostasis (phosphorylated 5'AMP-activated protein kinase/5'AMP-activated protein kinase) versus males. These data highlight that KD and exercise beneficially impacts hepatic metabolism and oxidative stress and merits further investigation. Novelty KD feeding combined with exercise improved hepatic oxidative stress, suppressed markers of de novo lipogenesis, and increased markers of mitochondrial content versus WD feeding. Males and females responded similarly to combined KD feeding and exercise. Female rats exhibited elevated hepatic markers of autophagy/mitophagy and energy homeostasis compared with male rats.