Metabolic and hormonal responses to nutritional ketosis across metabolic phenotypes and sex in adults

Abstract Ketogenic diets are increasingly used for weight management and metabolic improvement, but it remains unclear whether nutritional ketosis induces uniform adaptation across metabolic phenotypes and sex. This exploratory study examined phenotype- and sex-dependent responses to a 60-day ketogenic diet in adults with normal weight, overweight or obesity. Participants were stratified into six metabolic phenotype–sex groups and assessed at baseline, day 14, day 30 and day 60. Plasma biochemical and hormonal markers, appetite and perceived stress scores, and body composition were analyzed using repeated-measures models. During the ketogenic diet intervention, β-hydroxybutyrate increased in all groups, confirming nutritional ketosis, but the response differed between groups and was most progressive in men with obesity. Free fatty acids manifested in a heterogeneous manner, exhibiting distinct time-, phenotype-, and sex-dependent profiles. Glucose decreased after diet initiation, whereas insulin and HOMA-IR improved mainly in participants with overweight and obesity. Lipid profile changes were variable, while liver enzymes showed a sex-dependent temporal pattern. Appetite score differed by metabolic phenotype, leptin changed according to phenotype and sex, and ghrelin remained unchanged. Self-reported perceived stress scores showed group-specific changes, whereas cortisol changed over time and body mass, fat mass, visceral adipose tissue and subcutaneous adipose tissue decreased. These findings indicate that responses observed during the ketogenic diet intervention showed variable patterns across metabolic phenotypes and sex; however, given the limited sample size, these apparent between-group differences should be interpreted cautiously. Because of the single-arm design, these changes cannot be attributed to nutritional ketosis independently of weight loss or changes in energy intake.