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Signatures of metabolic diseases on spermatogenesis and testicular metabolism

Nature Reviews Urology (2024)Cite this article

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Abstract

Diets leading to caloric overload are linked to metabolic disorders and reproductive function impairment. Metabolic and hormonal abnormalities stand out as defining features of metabolic disorders, and substantially affect the functionality of the testis. Metabolic disorders induce testicular metabolic dysfunction, chronic inflammation and oxidative stress. The disruption of gastrointestinal, pancreatic, adipose tissue and testicular hormonal regulation induced by metabolic disorders can also contribute to a state of compromised fertility. In this Review, we will delve into the effects of high-fat diets and metabolic disorders on testicular metabolism and spermatogenesis, which are crucial elements for male reproductive function. Moreover, metabolic disorders have been shown to influence the epigenome of male gametes and might have a potential role in transmitting phenotype traits across generations. However, the existing evidence strongly underscores the unmet need to understand the mechanisms responsible for transgenerational paternal inheritance of male reproductive function impairment related to metabolic disorders. This knowledge could be useful for developing targeted interventions to prevent, counteract, and most of all break the perpetuation chain of male reproductive dysfunction associated with metabolic disorders across generations.

Key points

  • Diets rich in sugar and fat are associated with metabolic disorders and poor reproductive health.

  • The testis is highly sensitive to the metabolic status of the organism, as metabolic disorders promote metabolic and hormonal testicular dysregulation.

  • Metabolic disorders are associated with testicular fat accumulation, inflammation, and oxidative stress, which might trigger male reproductive dysfunction.

  • Hormonal imbalance stands out as a hallmark of obesity, with the gastrointestinal system and adipose tissue hormones having a pivotal role in testicular metabolism and function.

  • The epigenetic profile of male gametes is responsive to the metabolic state of the organism and is potentially inheritable, in turn predisposing the offspring to metabolic disorders and potentially prompting the transgenerational perpetuation of acquired metabolic disorders.

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Fig. 1: Fat accumulation in the adipose tissue — chronic inflammation and effect on testicular metabolism.
Fig. 2: High-fat diet-induced metabolic and hormonal testicular dysregulation.
Fig. 3: Putative signalling pathways involved in the energetic regulation of Sertoli cells by gut and adipose hormones.
Fig. 4: Overview of the proposed model of paternal inheritance of metabolic diseases.

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Acknowledgements

This work was supported by the Portuguese Foundation for Science and Technology: D.F. Carrageta (SFRH/BD/136779/2018 and COVID/BD/153209/2023), S.C. Pereira (2021.05487.BD), UMIB (UIDB/00215/2020 and UIDP/00215/2020), ITR (LA/P/0064/2020), IBiMED (UIDP/04501/2020 and UIDB/04501/2020) and LAQV/REQUIMTE (UIDB/50006/2020), co-funded by FEDER funds through the COMPETE/QREN, FSE/POPH, and POCI — COMPETE 2020 (POCI-01-0145-FEDER- 007491) funds; co-funded by the Portuguese Society of Diabetology (Sociedade Portuguesa de Diabetologia) through the Charneco da Costa Grant (2021).

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  1. These authors contributed equally: David F. Carrageta, Sara C. Pereira.

Authors and Affiliations

  1. Clinical and Experimental Endocrinology, UMIB - Unit for Multidisciplinary Research in Biomedicine, ICBAS - School of Medicine and Biomedical Sciences, University of Porto, Porto, Portugal

    David F. Carrageta, Sara C. Pereira & Mariana P. Monteiro

  2. Laboratory for Integrative and Translational Research in Population Health (ITR), University of Porto, Porto, Portugal

    David F. Carrageta, Sara C. Pereira & Mariana P. Monteiro

  3. Department of Pathology, Faculty of Medicine, University of Porto, Porto, Portugal

    Sara C. Pereira

  4. LAQV-REQUIMTE & Department of Chemistry, University of Aveiro, Campus Universitário de Santiago, Aveiro, Portugal

    Sara C. Pereira, Rita Ferreira & Pedro F. Oliveira

  5. Department of Medical Sciences, Institute of Biomedicine (iBiMED), University of Aveiro, Campus de Santiago Agra do Crasto, Aveiro, Portugal

    Marco G. Alves

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M.G.A., D.F.C. and S.C.P. researched data for the article. All authors contributed substantially to discussion of the content. All authors wrote the article. All authors reviewed and/or edited the manuscript before submission.

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Carrageta, D.F., Pereira, S.C., Ferreira, R. et al. Signatures of metabolic diseases on spermatogenesis and testicular metabolism. Nat Rev Urol (2024). https://doi.org/10.1038/s41585-024-00866-y

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