Sex Differences in Ketogenic Diet Response Reveal Gonadal Hormone Interaction With FGF21 in Mice

Although indicated as adjunctive therapy for seizure disorders, ketogenic diets (KDs) have gained popularity for weight loss and mitigating the metabolic risks associated with severe obesity. However, efficacy, durability, and long-term consequences are incompletely understood. In preclinical models, most studies have included only male mice, precluding an understanding of sex-specific responses to KD. In this study, we investigated sex differences in response to a high-fat, low carbohydrate, low-protein KD using male and female C57BL/6J mice. Despite equivalent circulating levels of β-hydroxybutyrate, male mice exhibited weight loss characterized by loss of fat mass and lean mass in concert with increased energy expenditure. In contrast, female mice exhibited increased fat mass and body weight on the KD. Male mice manifested increased insulin sensitivity, without reducing glucose excursions during glucose tolerance testing, in concert with decreased glucose-stimulated insulin release. In contrast, females developed glucose intolerance and insulin resistance relative to control females. Following oophorectomy, female mice lost weight on KD but remained glucose intolerant. Orchidectomy in male mice reversed weight loss in KD males. Circulating fibroblast growth factor 21 (FGF21) concentrations were increased in males but not females on KD and correlated with increased FGF21 expression in brown adipose tissue. These findings demonstrate that the metabolic effects of KD are sex-specific and suggest that gonadal hormones modulate the adaptive response to ketogenic diets via FGF21 signaling.