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Background <p>The rising prevalence of childhood obesity is a serious global public health issue and poses a significant threat to male reproductive health. Aromatase (CYP19A1) expression is often elevated in obese men, associated with diminished testosterone levels, but the underlying mechanisms linking childhood obesity to long-term male infertility remain poorly understood.</p> Methods <p>We conducted a multi-faceted study combining a cross-sectional clinical investigation, a Mendelian randomization (MR) analysis, bioinformatic analysis of public datasets, and a mechanistic animal study. The clinical study included 30 obese and 30 normal-weight prepubertal boys. Two-sample MR was used to infer the causal relationship between different classes of obesity and male infertility. Gene Expression Omnibus (GEO) datasets were analyzed to identify differentially expressed genes (DEGs) and pathways. A high-fat diet (HFD)-induced obese mouse model was established to validate the bioinformatic hypotheses by investigating the STAT3/CYP19A1 pathway.</p> Results <p>Clinically, obese boys exhibited significantly smaller testicular volume, shorter penis length, and lower levels of testosterone, LH, Inhibin B, and FSH (<i>P</i> &lt; 0.05). MR analysis revealed a significant causal relationship between childhood obesity (<i>P</i> = 0.038), class 1 obesity (<i>P</i> = 0.0423), and class 2 obesity (<i>P</i> = 0.0041) with male infertility. Bioinformatic analysis of fertility-related datasets implicated CYP19A1 as a key gene, while analysis of adipose tissue datasets highlighted inflammatory pathways. STAT3 was predicted and subsequently confirmed as a key transcription factor linking inflammation to CYP19A1 expression. The HFD-induced obese mouse model recapitulated the human phenotype, showing testicular damage, ectopic lipid deposition, increased apoptosis, and reduced testosterone. Molecularly, we confirmed a significant upregulation of STAT3 and CYP19A1 specifically in the epididymal adipose tissue of obese mice (<i>P</i> &lt; 0.05).</p> Conclusion <p>Our integrated findings suggest that childhood obesity is a causal risk factor for impaired male reproductive function. The mechanism involves a local, paracrine effect of inflamed epididymal adipose tissue, which promotes STAT3-mediated upregulation of CYP19A1, leading to increased local aromatization of androgens and subsequent testicular damage. This STAT3–CYP19A1–testosterone signaling pathway represents a potential therapeutic target for mitigating obesity-related male reproductive disorders.</p>

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Obesity impairs male reproductive development in prepubertal boys via local adipose tissue inflammation and the STAT3/CYP19A1 pathway

  • 期刊论文

  • 发表日期：

    2026年1月27日

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  • Wenbiao Han,
  • Mengnan Lu,
  • Yanhong Liu,
  • Yi Ding,
  • Chunyan Yin

摘要

Background

The rising prevalence of childhood obesity is a serious global public health issue and poses a significant threat to male reproductive health. Aromatase (CYP19A1) expression is often elevated in obese men, associated with diminished testosterone levels, but the underlying mechanisms linking childhood obesity to long-term male infertility remain poorly understood.

Methods

We conducted a multi-faceted study combining a cross-sectional clinical investigation, a Mendelian randomization (MR) analysis, bioinformatic analysis of public datasets, and a mechanistic animal study. The clinical study included 30 obese and 30 normal-weight prepubertal boys. Two-sample MR was used to infer the causal relationship between different classes of obesity and male infertility. Gene Expression Omnibus (GEO) datasets were analyzed to identify differentially expressed genes (DEGs) and pathways. A high-fat diet (HFD)-induced obese mouse model was established to validate the bioinformatic hypotheses by investigating the STAT3/CYP19A1 pathway.

Results

Clinically, obese boys exhibited significantly smaller testicular volume, shorter penis length, and lower levels of testosterone, LH, Inhibin B, and FSH (P < 0.05). MR analysis revealed a significant causal relationship between childhood obesity (P = 0.038), class 1 obesity (P = 0.0423), and class 2 obesity (P = 0.0041) with male infertility. Bioinformatic analysis of fertility-related datasets implicated CYP19A1 as a key gene, while analysis of adipose tissue datasets highlighted inflammatory pathways. STAT3 was predicted and subsequently confirmed as a key transcription factor linking inflammation to CYP19A1 expression. The HFD-induced obese mouse model recapitulated the human phenotype, showing testicular damage, ectopic lipid deposition, increased apoptosis, and reduced testosterone. Molecularly, we confirmed a significant upregulation of STAT3 and CYP19A1 specifically in the epididymal adipose tissue of obese mice (P < 0.05).

Conclusion

Our integrated findings suggest that childhood obesity is a causal risk factor for impaired male reproductive function. The mechanism involves a local, paracrine effect of inflamed epididymal adipose tissue, which promotes STAT3-mediated upregulation of CYP19A1, leading to increased local aromatization of androgens and subsequent testicular damage. This STAT3–CYP19A1–testosterone signaling pathway represents a potential therapeutic target for mitigating obesity-related male reproductive disorders.