Male hypogonadism causes obesity associated with impairment of hepatic gluconeogenesis in mice
Open accessAbstract
The steroid hormones synthesized by the male gonads play diverse roles in biological processes. Androgens, the primary hormones produced by the male gonads, are key regulators of fat homeostasis, hence androgen-deprivation therapies often induce obesity. However, the molecular mechanism by which male gonadal dysfunction leads to obesity remains unclear, because results from animal studies regarding fat accumulation in the context of gonadal defects do not reflect clinical findings. Here, we investigated the mechanism underlying the development of obesity in animals with male gonadal dysfunction by analyzing the long-term physiological changes in adult male mice with surgical castration. Nine weeks after surgery, white adipose tissue (WAT) mass was higher in the castrated (Cas) mice than in sham-operated (Sham) mice. In addition, castration induced hyperlipidemia and hyperglycemia. However, genes involved in lipid metabolism, including hormone-sensitive lipase, were unchanged in the adipose tissue of the Cas mice, despite the increase in WAT. In contrast, a hepatic gluconeogenesis gene, glucose-6-phosphatase, was significantly upregulated in the Cas mice than in Sham mice. Our findings suggest that long-term hypogonadism in mice mimics the effects in humans, and a potential molecular basis for the induction of obesity in this model is impairment of hepatic gluconeogenesis.
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Castrated male rodents have been shown to exhibit improved glucose and insulin tolerance with reduced adiposity in some studies, and in others display worsened adiposity, WAT inflammation, and glucose tolerance.
“By contrast, castrated male rodents have been shown to exhibit improved glucose and insulin tolerance with reduced adiposity in some studies (85, 86), and in others display worsened adiposity, WAT inflammation, and glucose tolerance (87, 88).”
From Metabolic impact of endogenously produced estrogens by adipose tissue in females and males across the lifespan (2025) · cites this paper as [87]
The Body Weight, Food Intake, and Tissue Weight section reports increased white adipose tissue relative to body weight nine weeks after castration, and the Serum Biochemical Markers section reports higher fasting glucose. The paper does not report WAT inflammation or a glucose-tolerance test, so it does not establish those parts of the worsened-outcomes claim. The improved-outcomes clause is attached to other citations, not this source. (LLM, conf=0.87)
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Additional file 1 of Castration promotes the browning of the prostate tumor microenvironment
Álvarez-Artime, A., García-Soler, B., González‐Menéndez, P., Fernández-Vega, S., Cernuda‐Cernuda, R., Hevia, D., Mayo, J. C., & Sáinz, R. M. S. D. L. M. (2023) · Figshare · doi:10.6084/m9.figshare.24217433
Additional file 2 of Castration promotes the browning of the prostate tumor microenvironment
Álvarez-Artime, A., García-Soler, B., González‐Menéndez, P., Fernández-Vega, S., Cernuda‐Cernuda, R., Hevia, D., Mayo, J. C., & Sáinz, R. M. S. D. L. M. (2024) · Figshare · doi:10.6084/m9.figshare.24217632
The regulation of intrahepatic fatty acid partitioning within the human liver: the effect of sex
Dennis, K. M. J. H., Start, C. A. T., Josh, D., & Hodson, L. (2026) · Clinical Science · doi:10.1042/cs20260180
- Authors
- Aoki, A., Fujitani, K., Takagi, K., Kimura, T., Nagase, H., & Nakanishi, T.
- Affiliations
- Gifu Pharmaceutical University (JP)
- Setsunan University (JP)
- Venue
- Biological & Pharmaceutical Bulletin
- Publisher
- Pharmaceutical Society of Japan
- Published
- 2016
- Volume
- 39
- Issue
- 4
- Pages
- 587-592
- ISSN
- 0918-6158 (ISSN-L)
- 1347-5215
- OpenAlex
- W2333975790
- Cited by
- 18
- References
- 35
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 1 · 2023: 2 · 2022: 2 · 2021: 1 · 2020: 5 · 2018: 1 · 2017: 4
- FWCI
- 1.67
- Type
- journal article
- Language
- en
- Open access
- diamond
- doi.org
- Locations
- Biological and Pharmaceutical Bulletin (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Society for the Promotion of Science (25281026, 15K14989, 25293031)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Hormonal and reproductive studies
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- male hypogonadism, obesity, hepatic gluconeogenesis, castration, androgen deprivation therapy, glucose-6-phosphatase, white adipose tissue, hyperlipidemia, hyperglycemia, hormone-sensitive lipase, gonadal dysfunction
- MeSH terms
- Animals, Blood Glucose, Body Weight, Eating, Fatty Acids, Nonesterified, Gluconeogenesis, Hyperglycemia, Hyperlipidemias, Hypogonadism, Liver, Male, Mice, Inbred C57BL, Obesity, Orchiectomy, Organ Size, Triglycerides, Adipose Tissue, White
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