TY  - EJOU
AU  - Du, Guowei 
AU  - Chen, Jianhuai 
AU  - Wang, Heng 
AU  - Chen, Shanshan 
AU  - Wang, Yanting 
AU  - Wang, Jing 
AU  - Yang, Guangzhao 
AU  - Liu, Siwen 
AU  - Chen, Xuanyi 

TI  - Diet-induced obesity disrupts hypothalamic- testicular NF-κB signaling axis and impairs spermatogenesis: an integrated transcriptomic analysis and meta-analysis
T2  - Canadian Journal of Urology

PY  - 
VL  - 
IS  - 
SN  - 1488-5581

AB  -  <b>Background:</b> 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. <b>Methods:</b> 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. <b>Results:</b> Integrated analysis revealed marked NF-κB transcriptional activity in testicular germ cells (predominantly round spermatids, adjusted <i>p</i> = 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 <i>p</i> &lt; 0.05). Concurrently, a high-fat diet was associated with hypothalamic NF-κB signaling (log<sub>2</sub>FC = 1.32, adjusted <i>p</i> = 0.012) and upregulated Protein Phosphatase 2 Catalytic Subunit Alpha (Ppp2ca; log<sub>2</sub>FC = 1.57, adjusted <i>p</i> = 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, <i>p</i> &lt; 0.001) and 3.24-fold higher azoospermia risk (95% CI:1.18–8.88, <i>p</i> = 0.023). <b>Conclusion:</b> 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.
KW  - diet-induced obesity; male infertility; nuclear factor kappa-B (NF-κB) signaling; hypothalamic-testicular axis; transcriptomic integration; meta-analysis

DO  - 10.32604/cju.2026.078745