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Updated: Mar 9, 2026
Assessment of Sexual Behavior of Male Mice
Published on: March 5, 2020
Deficient melanocortin-4 receptor causes abnormal reproductive neuroendocrine profile in female mice
Xiaolin Chen1,2, Lili Huang1, Hwee Y Tan1
1School of Biomedical ScienceUniversity of Queensland, St Lucia, Brisbane, Queensland, Australia.
Abstract:
Deletion of the melanocortin-4-receptor (Mc4r) gene in mice causes hyperphagia, followed by hyperinsulinemia, obesity and progressive infertility. Evidence shows that the number of developed corpora lutea is reduced in obese MC4R-knockout (MC4R KO) female mice, but the mechanism is unclear. The effect of hyperphagia and obesity by MC4R KO on pulsatile luteinizing hormone (LH) secretion and ovulation remains unknown. In MC4R KO mice and wild-type littermates (WT LM) during the diestrus period throughout different ages, we examined and monitored their metabolic status, pulsatile LH profiles, follicular morphology and the number of corpora lutea. MC4R KO mice were hyperphagic, obese, hyperglycemic, hyperinsulinemic and demonstrated insulin resistance and hepatic steatosis. Irregular estrous cycles and significant changes in the LH secretion profiles were observed in sexually matured 16- to 28-week MC4R KO mice, without any difference in testosterone levels. In addition, MC4R KO mice at 16 weeks of age had significantly fewer corpora lutea than same age WT LM mice. The ovary examinations of MC4R KO mice at 28 weeks of age showed predominantly antral and preovulatory follicles with no corpora lutea. These findings were consistent with the decrease in total, pulsatile, mass and basal LH releases in MC4R KO mice. The characteristics of hormone profiles in obese MC4R KO mice indicate that MC4R plays an important role in regulating LH release, ovulation and reproductive ability probably via hyperphagia-induced obesity. Further study of correlation between metabolic and reproductive regulatory hormones is warranted to dissect the pathological mechanism underlying obesity-induced infertility.Free Chinese abstract: A Chinese translation of this abstract is freely available at http://www.reproduction-online.org/content/153/3/267/suppl/DC1.
Insights
Melanocortin-4-receptor (MC4R) knockout mice exhibit hyperphagia and obesity, leading to irregular estrous cycles and reduced luteinizing hormone (LH) release. This impacts ovulation and fertility, suggesting MC4R
Area of Science:
- Reproductive Endocrinology
- Metabolic Syndrome
- Neuroendocrinology
Background:
- Melanocortin-4-receptor (MC4R) deficiency causes hyperphagia, obesity, and infertility in mice.
- The precise mechanisms linking MC4R deficiency, obesity, and reproductive dysfunction, particularly concerning luteinizing hormone (LH) secretion and ovulation, remain unclear.
Purpose of the Study:
- To investigate the impact of MC4R deficiency-induced hyperphagia and obesity on pulsatile LH secretion, ovulation, and corpus luteum formation in female mice.
- To elucidate the role of MC4R in regulating reproductive function in the context of metabolic disturbances.
Main Methods:
- Metabolic status, including weight, glucose, insulin, and liver fat, was monitored in MC4R knockout (MC4R KO) and wild-type littermate (WT LM) mice.
- Pulsatile LH secretion profiles were measured using blood sampling in sexually mature mice.
- Ovarian morphology and corpus luteum counts were assessed at different ages.
Main Results:
- MC4R KO mice displayed hyperphagia, obesity, hyperglycemia, hyperinsulinemia, insulin resistance, and hepatic steatosis.
- Sexually mature MC4R KO mice exhibited irregular estrous cycles and altered LH secretion patterns, with decreased total, pulsatile, mass, and basal LH release.
- MC4R KO mice had significantly fewer corpora lutea and predominantly immature follicles, indicating impaired ovulation.
Conclusions:
- MC4R plays a critical role in regulating LH release, ovulation, and reproductive capacity, likely mediated through hyperphagia-induced obesity.
- Obesity resulting from MC4R deficiency significantly disrupts the hypothalamic-pituitary-gonadal axis, leading to infertility.
- Further research is needed to understand the interplay between metabolic and reproductive hormones in obesity-induced infertility.
