Modeling sex-specific whole-body metabolic responses to feeding and fasting.

Men generally favor carbohydrate metabolism, while women lean towards lipid metabolism, resulting in significant sex-based differences in energy oxidation across various metabolic states such as fasting and feeding. These differences are influenced by body composition and inherent metabolic fluxes, including increased lipolysis rates in women. However, understanding how sex influences organ-specific metabolism and systemic manifestations remains incomplete. To address these gaps, we developed a sex-specific, whole-body metabolic model for feeding and fasting scenarios in healthy young adults. Our model integrates organ metabolism with whole-body responses to mixed meals, particularly high-carbohydrate and high-fat meals. Our predictions suggest that differences in liver and adipose tissue nutrient storage and oxidation patterns drive systemic metabolic disparities. We propose that sex differences in fasting hepatic glucose output may result from the different handling of free fatty acids, glycerol, and glycogen. We identified a metabolic pathway, possibly more prevalent in female livers, redirecting lipids towards carbohydrate metabolism to support hepatic glucose production. This mechanism is facilitated by the TG-FFA cycle between adipose tissue and the liver. Incorporating sex-specific data into multi-scale frameworks offers insights into how sex modulates human metabolism.