Ketogenic diet in combination with voluntary exercise impacts markers of hepatic metabolism and oxidative stress in male and female rats
Authors: Moore Mary P , Cunningham Rory P , Kelty Taylor J , Boccardi Luigi R , Nguyen Nhu R , Booth Frank W , Rector R. Scott 
Published: April 2020

IntroductionHigh‐fat, very low carbohydrate, ketogenic diets (KD) have been shown to benefit hepatic lipid metabolism; however, the effects of KD on hepatic metabolism when combined with regular exercise is unknown. Here, we investigated the effects of KD vs. high fat, high carbohydrate Western diet (WD) on markers of hepatic lipid metabolism and oxidative stress in voluntarily exercised male and female rats.MethodsMale and female Wistar rats (7 weeks of age) were given access to voluntary running wheels and randomized into three groups (n= 8–14) with standard chow (SC; 26.5%, 56.5%, 17%‐PRO, CHO, FAT), WD (15.2%, 42.7%, 42% & 0.2% cholesterol by weight) or KD (9.2%, 0.3%, 90.5%) for 7 weeks. WD and KD groups were pair‐fed to calorically match SC controls.ResultsKD and WD feeding (p≤0.05) decreased food intake (kcals/week) relative to SC fed in male but not in female rats, with KD fed males gaining less body weight vs. SC and WD males (p≤0.05). In addition, body fat percentage (BF%) was increased in WD and KD vs. SC in both males and females (p≤0.05), although female KD fed rats displayed a lower BF% relative to female WD. Female rats ran more than males (12.0±0.3 km/wk vs. 5.4±0.7 km/wk, p≤0.05). Liver triglycerides (TAGs) were higher in KD and WD fed animals vs. SC controls (p<0.001), but were attenuated in female KD vs. female WD rats (p<0.05). KD feeding dramatically suppressed hepatic protein markers of de novo lipogenesis [fatty acid synthase (FAS) and acetyl‐CoA carboxylase (ACC)], and increased markers of mitochondrial biogenesis/content; PGC‐1α, mitochondrial transcription factor A and citrate synthase activity in both males and females. KD feeding also increased the antioxidant enzyme glutathione peroxidase 1 (GPx1) vs. SC and WD in both males and females and lowered the antioxidant response factor nuclear factor E2‐related factor 2 (NRF2) vs. SC only within males. Interestingly, females exhibited elevated hepatic protein markers of mitophagy light chain 3 (LC3 II/I ratio), autophagy‐related protein (ATG 12:5) and cellular energy homeostasis (phospho‐ 5′ AMP‐activated protein kinase (AMPK)/AMPK ratio) with decreased NRF2 protein content (p<0.05) compared with males. On the other hand, protein content of markers of mitochondrial biogenesis/content PGC‐1α and oxidative phosphorylation‐Complex IV were lower (p<0.05) in females vs. males.ConclusionWhen compared with a Western‐style diet, KD feeding in combination with voluntary exercise in rats promoted improved body composition and hepatic oxidative stress, suppressed of markers of hepatic de novo lipogenesis, and increased markers of hepatic mitochondria content and function. These adaptations occurred in the presence of elevated hepatic TAGs. More thorough investigation of the molecular pathways activated by ketogenic diet feeding with exercise are warranted.Support or Funding InformationSupport: VA Merit Grant I01BX003271‐01 (R.S.R.).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.