Sex differences in energy metabolism: natural selection, mechanisms and consequences

Metabolic homeostasis operates differently in men and women. This sex asymmetry is the result of evolutionary adaptations that enable women to resist loss of energy stores and protein mass while remaining fertile in times of energy deficit. During starvation or prolonged exercise, women rely on oxidation of lipids, which are a more efficient energy source than carbohydrates, to preserve glucose for neuronal and placental function and spare proteins necessary for organ function. Carbohydrate reliance in men could be an evolutionary adaptation related to defence and hunting, as glucose, unlike lipids, can be used as a fuel for anaerobic high-exertion muscle activity. The larger subcutaneous adipose tissue depots in healthy women than in healthy men provide a mechanism for lipid storage. As female mitochondria have higher functional capacity and greater resistance to oxidative damage than male mitochondria, uniparental inheritance of female mitochondria may reduce the transmission of metabolic disorders. However, in women, starvation resistance and propensity to obesity have evolved in tandem, and the current prevalence of obesity is greater in women than in men. The combination of genetic sex, programming by developmental testosterone in males, and pubertal sex hormones defines sex-specific biological systems in adults that produce phenotypic sex differences in energy homeostasis, metabolic disease and drug responses. In this Review, Franck Mauvais-Jarvis discusses how adaptive selection during evolution could have shaped sex differences in energy partitioning, adipose tissue function and distribution, and glucose homeostasis. He also discusses the hormonal and genetic mechanisms that underlie these sex differences and their implications for metabolic disease and sex-based precision medicine. Females have evolved more efficient mechanisms than males to conserve energy and resist loss of energy stores and proteins in times of food scarcity or prolonged exercise.During starvation or prolonged exercise, the actions of oestrogens enable females to rely on lipid oxidation as an efficient energy source and preserve glucose for neuronal functions and proteins for organ functions.Healthy women have larger subcutaneous adipose depots than healthy men; these depots provide a mechanism for long-term lipid storage and starvation resistance.Females transmit healthy mitochondria with high functional capacity and thereby reduce the risk of heritable metabolic disorders in their offspring.In women, mechanisms of starvation resistance and propensity to obesity have evolved in tandem; in populations worldwide, the prevalence of obesity is greater in women than in men.Together, genetic sex, developmental programming by testosterone, and pubertal sex hormones define sex-specific biological systems that produce sex differences in energy homeostasis, metabolic disease and responses to anti-diabetic and anti-obesity drugs.