Intermittent fasting restores fertility dysfunction caused by a high-fat diet in male rats: role of SIRT-1/NRF2/P38 MAPK/NLRP3

Dalia A. Hemead; Nanees F. El-Malkey; Mohamed Aref; Nievin Ahmed Mahran; Esraa ElSheikh; Mohamed A. Nassan; Mohamed H. A. Gadelmawla; Gamal A. Salem; Amira F. A. Ahmed; Sahar M. El-Sayed; Eman H. Elsheikh; Nehal I. Hendy

doi:10.1071/RD24187

RESEARCH ARTICLE (Open Access)

Previous Contents Vol 37(14)

Intermittent fasting restores fertility dysfunction caused by a high-fat diet in male rats: role of SIRT-1/NRF2/P38 MAPK/NLRP3

Dalia A. Hemead ^A , Nanees F. El-Malkey ^A , Mohamed Aref

^B ^* , Nievin Ahmed Mahran ^C , Esraa ElSheikh ^B , Mohamed A. Nassan ^D , Mohamed H. A. Gadelmawla ^E , Gamal A. Salem ^F , Amira F. A. Ahmed ^G , Sahar M. El-Sayed ^B , Eman H. Elsheikh ^H and Nehal I. Hendy ^A

+ Author Affiliations

- Author Affiliations

^A Medical Physiology Department, Faculty of medicine, Zagazig University, El-Sharkia, Egypt.

^B Anatomy and Embryology Department, Faculty of Veterinary Medicine, Zagazig University, El-Sharkia 44519, Egypt.

^C Biochemistry Department, Faculty of Dentistry, Sinai University – Kantara Campus, Egypt.

^D Department of Clinical Laboratory Sciences, Turabah University College, Taif University, P.O. Box 11099, Taif 21944, Saudi Arabia.

^E Histology Department, Faculty of Dentistry, Sinai University, Kantara Campus, Egypt.

^F Department of Pharmacology, Faculty of Veterinary Medicine, Zagazig University, El-Sharkia 44519, Egypt.

^G Human Anatomy and Embryology, Faculty of Medicine, Zagazig University, El-Sharkia, Egypt.

^H Comparative Anatomy Department, Faculty of Science, Zagazig University, El-Sharkia, Egypt.

^* Correspondence to: Abdelazizanatomy11@gmail.com

Handling Editor: Graeme Martin

Reproduction, Fertility and Development 37, RD24187 https://doi.org/10.1071/RD24187

Submitted: 18 November 2024 Accepted: 11 August 2025 Published online: 26 August 2025

© 2025 The Author(s) (or their employer(s)). Published by CSIRO Publishing. This is an open access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND)

Abstract

Context

Intermittent fasting (IF) is a dietary approach against obesity; however, investigations on its role in male fertility showed contradictory results.

Aims

As nuclear factor erythroid 2-related factor 2 (NRF2)/mitogen-activated protein kinase p38 (MAPK)/nucleotide-binding oligomerization domain-like receptor with a pyrin domain 3 (NLRP3) signaling pathways regulate inflammation and pyrotosis, this study aimed to elucidate whether these pathways are involved in the underlying molecular mechanisms and to investigate the prophylactic effects of IF on male reproduction dysfunction in obese rats.

Methods

Twenty-four adult rats were divided as follows: Control lean (CL), control positive (CP), which were fed standard diet for four non-consecutive days/week, with alternate fasting on the other 3 days (24 h fasting), high-fat diet group (HFD), and the HFD-fasting group (HFD-IF), which was fed a HFD, followed by fasting protocol as in CP group. Serum testosterone, inflammatory markers, semen analysis, testicular malondialdehyde (MDA) concentration, and superoxide dismutase (SOD) activity were measured. Also, testicular and epididymal histological study, immunohistochemical analysis of NLRP3 and NRF2 and reverse-transcription quantitative polymerase chain reaction (RT-qPCR) for mRNA expression of SIRT1, NRF2, p38AMPK and NLRP3 were performed.

Key results

Combining IF with HFD limited rats’ testicular spermatic and steroidogenesis impairment, histopathological alterations, by upregulating SIRT1/NRF2 and downregulating p38 MAPK/NLRP3 signaling pathways versus the HFD group. In the HFD-IF group, oxidative and inflammatory markers had a significant decrease versus in the HFD group.

Conclusions

IF has a beneficial effect on male reproductive health and emphasizes the significance of customized dietary strategies for addressing male fertility issues.

Implications

Further investigation is required to clarify more prophylactic mechanisms of IF.

Keywords: fertility, HFD, intermittent fasting, NLRP3, NRF2, P38 MAPK, SIRT-1, testis.

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