title: Deficient melanocortin-4 receptor causes abnormal reproductive neuroendocrine profile in female mice.
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.
authors.affiliation: School of Biomedical ScienceUniversity of Queensland, St Lucia, Brisbane, Queensland, Australia.|Endocrinology DepartmentRenmin Hospital of Wuhan University, Wuchang District, Wuhan, Hubei Province, People's Republic of China.
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Chen
authors.affiliation: School of Biomedical ScienceUniversity of Queensland, St Lucia, Brisbane, Queensland, Australia.
authors.forename: Lili
authors.initials: L
authors.lastname: Huang
authors.affiliation: School of Biomedical ScienceUniversity of Queensland, St Lucia, Brisbane, Queensland, Australia.
authors.forename: Hwee Y
authors.initials: HY
authors.lastname: Tan
authors.affiliation: School of Biomedical ScienceUniversity of Queensland, St Lucia, Brisbane, Queensland, Australia.
authors.forename: Hongzhuo
authors.initials: H
authors.lastname: Li
authors.affiliation: School of Biomedical ScienceUniversity of Queensland, St Lucia, Brisbane, Queensland, Australia.
authors.forename: Ying
authors.initials: Y
authors.lastname: Wan
authors.affiliation: Department of PhysiologyMonash University, Clayton, Victoria, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Cowley
authors.affiliation: Endocrine Research UnitMayo School of Graduate Medical Education, Clinical Translational Science Center, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Johannes D
authors.initials: JD
authors.lastname: Veldhuis
authors.affiliation: School of Biomedical ScienceUniversity of Queensland, St Lucia, Brisbane, Queensland, Australia chen.chen@uq.edu.au.
authors.forename: Chen
authors.initials: C
authors.lastname: Chen
mesh_terms: D000818:Animals; D003338:Corpus Luteum / Q000503:physiopathology*; D005234:Fatty Liver / Q000209:etiology / Q000378:metabolism / Q000473:pathology*; D005260:Female; D006943:Hyperglycemia / Q000209:etiology / Q000473:pathology; D006946:Hyperinsulinism / Q000209:etiology / Q000473:pathology; D007333:Insulin Resistance; D007986:Luteinizing Hormone / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009490:Neurosecretory Systems; D010053:Ovary / Q000503:physiopathology; D010060:Ovulation / Q000502:physiology; D044105:Receptor, Melanocortin, Type 4 / Q000502:physiology*; D012098:Reproduction / Q000502:physiology*
chemical_list: C574273:MC4R protein, mouse; D044105:Receptor, Melanocortin, Type 4; D007986:Luteinizing Hormone