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Sex Differences in Ketogenic Diet Response Reveal Gonadal Hormone Interaction With FGF21 in Mice
Yuan Zhang1,2, Jesse D Cochran2,3, Rhonda A Souvenir1,2
1Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA.
Abstract:
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.
Insights
Ketogenic diets (KDs) show sex-specific metabolic effects. Male mice lost weight and improved insulin sensitivity, while females gained weight and developed insulin resistance, influenced by gonadal hormones and FGF21.
Area of Science:
- Metabolic research
- Endocrinology
- Nutritional science
Background:
- Ketogenic diets (KDs) are popular for weight loss but their long-term effects and sex-specific responses are unclear.
- Preclinical studies often lack sex-specific data, limiting understanding of KD impacts.
- Investigating sex differences in KD response is crucial for personalized nutrition and metabolic health.
Purpose of the Study:
- To investigate sex-specific metabolic responses to a high-fat, low-carbohydrate, low-protein ketogenic diet (KD) in mice.
- To explore the role of gonadal hormones and FGF21 signaling in mediating these sex-specific effects.
- To compare the effects of KD on body weight, body composition, energy expenditure, glucose metabolism, and insulin sensitivity between male and female mice.
Main Methods:
- Utilized male and female C57BL/6J mice fed a specific KD formulation.
- Assessed body weight, body composition, energy expenditure, and glucose tolerance.
- Measured circulating β-hydroxybutyrate, insulin, FGF21, and performed glucose tolerance tests.
- Included surgical interventions: oophorectomy in females and orchidectomy in males.
Main Results:
- Male mice lost fat and lean mass with increased energy expenditure and improved insulin sensitivity, despite unchanged glucose excursions.
- Female mice gained fat mass and body weight, developing glucose intolerance and insulin resistance.
- Hormonal interventions (oophorectomy/orchidectomy) modulated KD effects on weight and glucose metabolism.
- Increased FGF21 levels in males correlated with brown adipose tissue expression, but not in females.
Conclusions:
- Ketogenic diet (KD) exerts sex-specific metabolic effects, impacting weight, body composition, and glucose homeostasis differently in males and females.
- Gonadal hormones play a significant role in modulating adaptive responses to ketogenic diets.
- FGF21 signaling, particularly in males, appears involved in the sex-specific metabolic adaptations to KD.
