Modelling sex-specific whole-body metabolic responses to feeding and fasting

Men exhibit a preference for carbohydrate metabolism, whereas women tend to favor lipid metabolism. Significant sex-based differences in energy oxidation are evident across various metabolic states, including fasting and feeding. While some of these differences can be attributed to variations in body composition--such as increased fat mass in women and higher muscle mass in men--there are also inherent disparities in metabolic fluxes. For instance, women exhibit increased rates of lipolysis independent of body composition. However, there remain gaps in our understanding of how sex influences the metabolism of specific organs and how these differences manifest at the systemic level. To address some of these gaps, we developed a sex-specific, whole-body, multi-scale model of metabolism during feeding and fasting. Our model represents healthy young adults (male and female) and integrates cellular metabolism in organs with whole-body responses following various mixed meals, particularly high-carbohydrate and high-fat meals. We explored sex-related variations in metabolic responses during both the absorptive and postabsorptive phases following meals. Our model predicted that sex-related metabolic differences observed at the systemic level are driven by variations in nutrient storage and oxidation patterns in the liver, skeletal muscle, and adipose tissue. We hypothesized that sex differences in hepatic glucose output during short-term fasts are partly influenced by variations in free fatty acids, glycerol, and glycogen handling. We also identified a candidate mechanism, possibly more prevalent in the female liver, where lipids are redirected toward carbohydrate metabolism to support hepatic glucose production. Integrating sex-specific data and parameters into multi-scale frameworks holds promise for enhancing our understanding of human metabolism and its modulation by sex. Author summaryMen and women exhibit different metabolic preferences, with men favoring carbohydrate metabolism and women favoring lipid metabolism. These differences impact energy usage during fasting and feeding, influenced by body composition and inherent metabolic variations. However, there remain gaps in our understanding of how sex influences the metabolism of specific organs and how these differences manifest at the systemic level. To address these gaps, we developed a sex-specific whole-body metabolic model, representing healthy young adults. Our model explores how men and women metabolize mixed meals, especially high-carbohydrate and high-fat meals. We found that sex-related metabolic variations arise from differences in nutrient storage and utilization in key organs like the liver, muscles, and fat tissue. We propose that variations in free fatty acids and glycogen handling contribute to differences in hepatic glucose output between men and women during short-term fasting. Integrating sex-specific data into metabolic models can enhance our understanding of human metabolism and its modulation by sex.