Effects of Leptin and Melanocortin Signaling Interactions on Pubertal Development and Reproduction
Open accessAbstract
Leptin and melanocortin signaling control ingestive behavior, energy balance, and substrate utilization, but only leptin signaling defects cause hypothalamic hypogonadism and infertility. Although GnRH neurons do not express leptin receptors, leptin influences GnRH neuron activity via regulation of immediate downstream mediators including the neuropeptides neuropeptide Y and the melanocortin agonist and antagonist, α-MSH, agouti-related peptide, respectively. Here we show that modulation of melanocortin signaling in female db/db mice through ablation of agouti-related peptide, or heterozygosity of melanocortin 4 receptor, restores the timing of pubertal onset, fertility, and lactation. Additionally, melanocortin 4 receptor activation increases action potential firing and induces c-Fos expression in GnRH neurons, providing further evidence that melanocortin signaling influences GnRH neuron activity. These studies thus establish melanocortin signaling as an important component in the leptin-mediated regulation of GnRH neuron activity, initiation of puberty and fertility.
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α-MSH via MC4 increases GnRH firing, while β-endorphin via μ-opioid receptors inhibits GnRH excitability.
“α-MSH activation of the melanocortin 4 (MC4) receptor increases GnRH action potential firing while β-endorphin signaling through μ-opioid receptors inhibit GnRH excitability33,59.”
From Emerging insights into hypothalamic‐pituitary‐gonadal axis regulation and interaction with stress signalling (2018) · cites this paper as [59]
In “Activation of melanocortin receptors increases GnRH neuron activity” (page not specified), the paper reports increased GnRH firing after treatment with MTII, an MC3/4 receptor agonist; it also reports MC4R expression in GnRH neurons. It does not establish that α-MSH acting specifically through MC4R caused the firing increase, and the passages found do not address β-endorphin inhibition through μ-opioid receptors (searched: endorphin, opioid). (LLM, conf=0.87)
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UTJECAJ LEPTINA NA HORMONALNU REGULACIJU REPRODUKTIVNOG SUSTAVA KRMAČA
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- Authors
- Israel, D. D., Sheffer-Babila, S., de Luca, C., Jo, Y.-H., Liu, S. M., Xia, Q., Spergel, D. J., Dun, S. L., Dun, N. J., & Chua, S. C.
- Affiliations
- Departments of Medicine (D.D.I., Y.-H.J., S.M.L., Q.X., S.C.C.), Bronx, New York 10461
- Albert Einstein College of Medicine (US)
- Department of Medicine (C.d.L.), Division of Preventive Medicine and Nutrition, Columbia University, New York, New York 10032
- Yale University (US)
- Temple University (US)
- Corresponding author
- Chua, Streamson C.
- Venue
- Endocrinology
- Publisher
- The Endocrine Society
- Published
- 2012-03-09
- Volume
- 153
- Issue
- 5
- Pages
- 2408-2419
- ISSN
- 0013-7227 (ISSN-L)
- 1945-7170
- PMC
- PMC3381095
- OpenAlex
- W2048438803
- Cited by
- 109
- References
- 76
- Citations by year
- 2026: 4 · 2025: 7 · 2024: 2 · 2023: 3 · 2022: 6 · 2021: 5 · 2020: 8 · 2019: 8 · 2018: 10 · 2017: 9 · 2016: 3 · 2015: 10 · 2014: 12 · 2013: 14 · 2012: 7
- FWCI
- 16.01
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Endocrinology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK057621, P30DK02668, T32DK007513)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD053529, U54HD058155)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Hypothalamic control of reproductive hormones
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Reproductive Biology and Fertility
- Keywords
- leptin signaling, melanocortin signaling, melanocortin-4 receptor, agouti-related protein, GnRH neurons, puberty onset, female fertility, hypothalamic hypogonadism, db/db mice, neuropeptide Y, alpha-melanocyte-stimulating hormone, c-fos, lactation, energy balance
- MeSH terms
- Animals, Blood Glucose, Cell Count, Estradiol, Female, Hypothalamus, Insulin, Neurons, Ovary, Progesterone, Sexual Maturation, Signal Transduction, Mice, Knockout, Leptin, Mice, Agouti-Related Protein, Receptors, Leptin
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