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ARTICLE
Diet-induced obesity disrupts hypothalamic- testicular NF-κB signaling axis and impairs spermatogenesis: an integrated transcriptomic analysis and meta-analysis
Guowei Du1,#, Jianhuai Chen2,#, Heng Wang3, Shanshan Chen1, Yanting Wang1, Jing Wang1, Guangzhao Yang4, Siwen Liu5,*, Xuanyi Chen1,*
1 Department of Reproduction, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
2 Department of Andrology, Jiangsu Province Hospital of Chinese Medicine, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, China
3 Department of Urology, Suzhou Hospital, Xiyuan Hospital of China Academy of Chinese Medical Sciences, Suzhou, China
4 Department of Andrology, Suzhou TCM Hospital Affiliated to Nanjing University of Chinese Medicine, Suzhou, China
5 Department of Oncology, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China
* Corresponding Author: Siwen Liu. Email: 
; Xuanyi Chen. Email: 
# Guowei Du and Jianhuai Chen are co-first authors
(This article belongs to the Special Issue: Metabolic and Lifestyle Influences on Urologic Health)
Canadian Journal of Urology https://doi.org/10.32604/cju.2026.078745
Received 07 January 2026; Accepted 14 April 2026; Published online 20 May 2026
Abstract
Background: Obesity is a recognized risk factor for male infertility, yet the involvement of the hypothalamic-testicular axis and nuclear factor kappa-B (NF-κB)-mediated inflammation remains incompletely defined. This study aimed to investigate whether diet-induced obesity is associated with alterations in the hypothalamic-testicular NF-κB signaling axis and spermatogenesis through integrated transcriptomic analysis and clinical meta-analysis. Methods: Testicular single-cell RNA-seq and hypothalamic transcriptomic data from diet-induced obese mice were integrated to identify cell-type-specific transcriptional changes. The analyses included differential expression, pathway enrichment, and NF-κB activity scoring based on target gene expression. Mechanistic findings related to steroidogenesis and germ-cell maturation were elucidated via integrated transcriptomic analysis, and a systematic clinical meta-analysis was further performed to validate these mechanistic insights and assess the association between obesity, sperm quality, and NF-κB-related inflammation in humans. Results: Integrated analysis revealed marked NF-κB transcriptional activity in testicular germ cells (predominantly round spermatids, adjusted p = 0.00134), whose median score was 1.82-fold higher than that of the control group. This activity inversely correlated with genes essential for steroidogenesis (Hsd3b1: r = −0.47 to −0.62), blood-testis barrier (BTB) integrity (Cldn11: r ≈ −0.55), and germ-cell maturation (Tnp1: r = −0.42 to −0.58; all adjusted p < 0.05). Concurrently, a high-fat diet was associated with hypothalamic NF-κB signaling (log2FC = 1.32, adjusted p = 0.012) and upregulated Protein Phosphatase 2 Catalytic Subunit Alpha (Ppp2ca; log2FC = 1.57, adjusted p = 0.008). Meta-analysis of 7 clinical studies confirmed obesity-associated reduced sperm concentration (standardized mean difference = −0.24, 95% CI: −0.37 to −0.12, p < 0.001) and 3.24-fold higher azoospermia risk (95% CI:1.18–8.88, p = 0.023). Conclusion: Collectively, these findings suggest that NF-κB-mediated inflammation along the hypothalamus-testis axis may contribute to obesity-related male infertility and highlight NF-κB as a potential therapeutic target. However, further interventional studies using NF-κB inhibitors or germ cell-specific genetic models are required to establish causality and validate NF-κB as a therapeutic target.
Keywords
diet-induced obesity; male infertility; nuclear factor kappa-B (NF-κB) signaling; hypothalamic-testicular axis; transcriptomic integration; meta-analysis
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