Male and Female Mice Respond Differently to Short-term Ketogenic Diet

The ketogenic diet (KD) is a high-fat, low-carbohydrate diet that results in the elevation of ketone bodies in the blood, known as ketosis. This metabolic consequence has been suggested as a method for treating neurological conditions, improving exercise performance, and facilitating weight loss. Since most research studies primarily use male populations, less information is available regarding potential sex differences in response to various interventions. Therefore, the purpose of this study was to explore the sex differences in physical, metabolic, and motor performance in mice fed the KD. Male (n=29) and female (n=26) C57BL/6 were randomly assigned to KD (90% fat, 1% carbohydrate) or chow (13% fat, 60% carbohydrate) group for 6 weeks. Body weight and food intake were tracked weekly. At baseline and every 2 weeks, the Rotarod performance test assessed motor coordination and activity levels in all mice. After 6 weeks, adipose tissue, quadriceps, and heart were weighed to observe changes in organ mass. Triglyceride (TG) was measured in the heart, liver, and quadriceps. Blood was drawn to measure changes in serum metabolite levels. Final body weights in Male-KD were similar to Male-chow; however, Female-KD mice were significantly higher relative to Female-chow. Although adipose tissue mass increased significantly in both KD groups, the increase was ~40% higher in Female-KD. Quadriceps mass was lower in Male-KD compared to Male-chow (188±6 vs.169±5 mg, P<0.05) while not statistically different in Female-KD relative to Female-chow. In contrast, heart weight to tibia length ratios (HW:TL) were increased in Female-KD compared to Female-chow (5.08±0.06 vs.5.58±0.12, P<0.05) with no significant change in Male-KD. The KD resulted in similar measures of ketosis, glucose intolerance, and hyperlipidemia in Male-KD and Female-KD. While cardiac TG content tended to increase in Male-KD and Female-KD to a similar extent (P<0.10), the increase in hepatic TG content was ~30% lower in Female-KD (P<0.05 vs. Male-KD). Although Rotarod performance was higher in Female-KD compared to Male-KD at week 2 (28.6±3.1 vs.15.2±1.6 sec, P<0.05), performance decreased in Female-KD and increased in Male-KD over the remaining weeks and was similar at week 6 (25.7±2.0 vs.20.7±2.0 sec). In summary, these data show sex specific differences in weight gain, adiposity, and muscle (i.e., cardiac and skeletal) mass changes in response to a short-term KD. Moreover, the data suggest that male and female mice on the KD differ in time sensitive adaptation to ketosis and motor activity. Since both males and females increase adiposity, develop glucose intolerance, and hyperlipidemia, this study questions the viability of the KD as a potential tool for weight loss, and importantly, highlights sex differences in the adaptation to the KD. © FASEB.