Sex Differences in the Response of C57BL/6 Mice to Ketogenic Diets

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 obesity. Typical KD are very low in carbohydrate and high in fat, promoting hepatic production of ketone bodies. Few studies have evaluated gender differences in response to KD, and many animal studies tend to be performed in male mice. 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 and 5.05-fold, p<10^-4 and p<0.01 respectively) with higher concentrations in females. After 8 weeks, 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 analysis revealed elevated lean mass in 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) relative to females on CD (p<0.001). 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 ± 10.3 mg/dl, p<0.05). However, after 120 minutes, blood glucose levels returned to initial fasting levels.

In conclusion, significant sex differences exist in terms of body composition and metabolism in response to ketogenic diets via mechanisms that remain to be elucidated.