Reproductive tissues maintain insulin sensitivity in diet-induced obesity
Open accessAbstract
Reproductive dysfunction is associated with obesity. We previously showed that female mice with diet-induced obesity (DIO) exhibit infertility and thus serve as a model of human polycystic ovary syndrome (PCOS). We postulated that differential insulin signaling of tissues leads to reproductive dysfunction; therefore, a comparison of insulin signaling in reproductive tissues and energy storage tissues was performed. Pituitary-specific insulin receptor knockout mice were used as controls. High-fat diet-induced stress, which leads to insulin resistance, was also investigated by assaying macrophage infiltration and phosphorylated Jun NH(2)-terminal kinase (pJNK) signaling. In lean mice, reproductive tissues exhibited reduced sensitivity to insulin compared with peripheral metabolic tissues. However, in obese mice, where metabolic tissues exhibited insulin resistance, the pituitary and ovary maintained insulin sensitivity. Pituitaries responded to insulin through insulin receptor substrate (IRS)2 but not IRS1, whereas in the ovary, both IRS1 and IRS2 were activated by insulin. Macrophage infiltration and pJNK signaling were not increased in the pituitary or ovary of lean mice relative to DIO mice. The lack of inflammation and cytokine signaling in the pituitary and ovary in DIO mice compared with lean mice may be one of the reasons that these tissues remained insulin sensitive. Retained sensitivity of the pituitary and ovary to insulin may contribute to the pathophysiology of PCOS.
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In PCOS, liver, skeletal muscle, and adipose tissue exhibit insulin resistance, whereas steroid-producing tissues and the pituitary retain insulin sensitivity.
“This leads to the paradox of insulin signaling in PCOS; liver, skeletal muscle, and adipose tissue exhibit IR, whereas steroid-producing tissues and the pituitary retain insulin sensitivity [71, 72].”
From Polycystic Ovary Syndrome: Pathophysiology, Presentation, and Treatment With Emphasis on Adolescent Girls (2019) · cites this paper as [72]
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- Authors
- Wu, S., Divall, S., Wondisford, F., & Wolfe, A.
- Affiliations
- Johns Hopkins University (US)
- Corresponding author
- Wu, Sheng
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2011-12-12
- Volume
- 61
- Issue
- 1
- Pages
- 114-123
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC3237653
- OpenAlex
- W2157301576
- Cited by
- 65
- References
- 42
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 5 · 2023: 3 · 2022: 3 · 2021: 5 · 2020: 2 · 2019: 5 · 2018: 7 · 2017: 4 · 2016: 4 · 2015: 5 · 2014: 9 · 2013: 6 · 2012: 2
- FWCI
- 6.07
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- Johns Hopkins University
- Endocrine Fellows Foundation
- National Institutes of Health (5p60dk079637-02, P60-DK079637)
- National Institute of Diabetes and Digestive and Kidney Diseases (P60 DK-079637, P30DK079637)
- National Institute of Child Health and Human Development
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD41859, U54HD041859, R01 HD44608, R01HD044608)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- insulin sensitivity, diet-induced obesity, polycystic ovary syndrome, reproductive disorders, insulin resistance, pituitary gland, ovary, insulin receptor substrate 2, IRS-1, insulin signaling, JNK signaling, macrophage infiltration, inflammation, infertility, high-fat diet
- MeSH terms
- Animals, Blood Glucose, Diet, Female, Genitalia, Insulin, Insulin Resistance, Mice, Inbred C57BL, Mice, Obese, Models, Biological, Obesity, Ovary, Pituitary Gland, Reproduction, Mice, Knockout, Mice, Diet, High-Fat
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