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

Nature Reviews Nephrology volume 20, pages 56–69 (2024)Cite this article

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Abstract

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.

Key points

  • 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.

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Fig. 1: Summary of sex differences in energy metabolism.
Fig. 2: Sex differences in the pathogenesis of type 2 diabetes mellitus (T2DM).
Fig. 3: Testosterone-induced epigenetic programming of metabolic homeostasis.
Fig. 4: Males and females represent different biological systems.

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Acknowledgements

The author’s work is supported by National Institutes of Health grant DK074970, Department of Veterans Affairs Merit Awards BX003725 and BX005218, and the Tulane Center of Excellence in Sex-Based Biology & Medicine.

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  1. Section of Endocrinology and Metabolism, John W. Deming Department of Medicine, Tulane University School of Medicine and Tulane Center of Excellence in Sex-Based Biology & Medicine, New Orleans, LA, USA

    Franck Mauvais-Jarvis

  2. Endocrine service, Southeast Louisiana Veterans Health Care System, New Orleans, LA, USA

    Franck Mauvais-Jarvis

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Mauvais-Jarvis, F. Sex differences in energy metabolism: natural selection, mechanisms and consequences. Nat Rev Nephrol 20, 56–69 (2024). https://doi.org/10.1038/s41581-023-00781-2

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