Abstract
Since the initial use of ketogenic diets (KD) as adjunctive treatment for epilepsy, these diets are being increasingly used to promote weight loss and to reduce the risk of metabolic sequelae of severe obesity. Typical KD are very low in carbohydrate and high in fat, promoting hepatic production of ketone bodies. Most animal studies tend to be performed in male mice, and few studies have evaluated gender differences in response to KD. To explore sex differences in response to KD, female and male wild-type mice on the C57BL/6J background were fed either a control diet (CD- 7% fat, 47% carb., 19% protein) or KD (75% fat, 3% carb., 8% protein), following weaning. Females on the CD manifested higher levels of circulating β-hydroxybutyrate (β-HB) than males (2.86-fold, p<0.05). Circulating β-HB concentrations increased with KD in males and females (1.30-fold & 5.05-fold, p<10(-4) & p<0.01 respectively) with higher concentrations in females. After 15 weeks of feeding, females on KD displayed an increase in body weight (1.07-fold KD vs. CD, p<0.05) while body weight declined in males (0.88-fold, p<0.05). Nuclear magnetic resonance (NMR) analysis revealed elevated lean mass in 18-week old females (1.07-fold, p<0.05), but a significant reduction in fat mass in males (0.49-fold, p<0.05) relative to sex-matched mice on CD. The female mice on KD developed impaired glucose tolerance with a 1.35-fold increase in glucose tolerance test area under the curve (GTT AUC) (p<0.001) relative to CD females. In contrast, fasting glucose levels were lower in males on KD (131.8 ± 12.5 mg/ dl vs. 169.2 ± 6.3 mg/dl, p<0.05). Despite no significant change in GTT AUC, the male mice on KD displayed elevated blood glucose concentrations 30 minutes after injection relative to males on CD (344.9 ± 18.7 mg/ dl vs. 272.0 ± 10.31 mg/dl, p<0.05). However, after 120 minutes, blood glucose levels returned to initial levels. To further investigate the role of estrogen in this sexual dimorphism, female mice were ovariectomized (OVX) and randomized to receive either a CD or KD after weaning. At 15 weeks old, OVX mice on KD displayed decreased body weight (0.84-fold, p<0.0001) and fat mass (0.65-fold, p<0.001) relative to CD-fed mice. Despite changes in body composition, OVX mice on KD still exhibited impaired glucose tolerance with a 1.4-fold increase in GTT AUC comparable to OVX mice on CD (p<0.05). In conclusion, significant sex differences exist in terms of body composition and metabolism in response to ketogenic diet, which may partially be attributed to estrogen.