POMC neurons control fertility through differential signaling of MC4R in kisspeptin neurons
Inactivating mutations in the melanocortin 4 receptor (MC4R) gene cause monogenic obesity. Interestingly, female patients also display various degrees of reproductive disorders, in line with the subfertile phenotype of Mc4r KO female mice. However, the cellular mechanisms by which MC4R regulates rep...
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eLife Sciences Publications Ltd
2025-07-01
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| Online Access: | https://elifesciences.org/articles/100722 |
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| author | Rajae Talbi Todd L Stincic Kaitlin Ferrari Choi Ji Hae Karol Walec Elizabeth Medve Achi Gerutshang Silvia Leon Elizabeth A McCarthy Oline K Rønnekleiv Martin J Kelly Victor M Navarro |
| author_facet | Rajae Talbi Todd L Stincic Kaitlin Ferrari Choi Ji Hae Karol Walec Elizabeth Medve Achi Gerutshang Silvia Leon Elizabeth A McCarthy Oline K Rønnekleiv Martin J Kelly Victor M Navarro |
| author_sort | Rajae Talbi |
| collection | DOAJ |
| description | Inactivating mutations in the melanocortin 4 receptor (MC4R) gene cause monogenic obesity. Interestingly, female patients also display various degrees of reproductive disorders, in line with the subfertile phenotype of Mc4r KO female mice. However, the cellular mechanisms by which MC4R regulates reproduction are unknown. Kiss1 neurons directly stimulate gonadotropin-releasing hormone (GnRH) release through two distinct populations: the Kiss1ARH neurons, controlling GnRH pulses, and the sexually dimorphic Kiss1AVPV/PeN neurons controlling the preovulatory luteinizing hormone (LH) surge. Here, we show that Mc4r expressed in Kiss1 neurons regulates fertility in females. In vivo, deletion of Mc4r from Kiss1 neurons in female mice replicates the reproductive impairments of Mc4r KO mice without inducing obesity. Conversely, re-insertion of Mc4r in Kiss1 neurons of Mc4r null mice restores estrous cyclicity and LH pulsatility without reducing their obese phenotype. In vitro, we dissect the specific action of Mc4r on Kiss1ARH versus Kiss1AVPV/PeN neurons and show that Mc4r activation excites Kiss1ARH neurons through direct synaptic actions. In contrast, Kiss1AVPV/PeN neurons are normally inhibited by MC4R activation except under elevated estradiol levels, thus facilitating the activation of Kiss1AVPV/PeN neurons to induce the LH surge driving ovulation in females. Our findings demonstrate that POMCARH neurons acting through MC4R directly regulate reproductive function in females by stimulating the ‘pulse generator’ activity of Kiss1ARH neurons and restricting the activation of Kiss1AVPV/PeN neurons to the time of the estradiol-dependent LH surge, and thus unveil a novel pathway of the metabolic regulation of fertility by the melanocortin system. |
| format | Article |
| id | doaj-art-ed4b2778a46941d4ab244e78fecb2ef4 |
| institution | DOAJ |
| issn | 2050-084X |
| language | English |
| publishDate | 2025-07-01 |
| publisher | eLife Sciences Publications Ltd |
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| series | eLife |
| spelling | doaj-art-ed4b2778a46941d4ab244e78fecb2ef42025-08-20T02:39:43ZengeLife Sciences Publications LtdeLife2050-084X2025-07-011310.7554/eLife.100722POMC neurons control fertility through differential signaling of MC4R in kisspeptin neuronsRajae Talbi0https://orcid.org/0000-0001-7158-6246Todd L Stincic1https://orcid.org/0000-0001-7504-2422Kaitlin Ferrari2Choi Ji Hae3Karol Walec4Elizabeth Medve5Achi Gerutshang6Silvia Leon7Elizabeth A McCarthy8Oline K Rønnekleiv9https://orcid.org/0000-0003-1841-4386Martin J Kelly10https://orcid.org/0000-0002-8633-2510Victor M Navarro11https://orcid.org/0000-0002-5799-219XHarvard Medical School, Boston, United States; Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Boston, United StatesDepartment of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, United StatesDivision of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Boston, United StatesDivision of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Boston, United StatesDivision of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Boston, United StatesDivision of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Boston, United StatesDivision of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Boston, United StatesHarvard Medical School, Boston, United States; Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Boston, United StatesHarvard Medical School, Boston, United States; Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Boston, United StatesDepartment of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, United States; Division of Neuroscience, Oregon National Primate Research Center, Beaverton, United StatesDepartment of Chemical Physiology and Biochemistry, Oregon Health & Science University, Portland, United States; Division of Neuroscience, Oregon National Primate Research Center, Beaverton, United StatesHarvard Medical School, Boston, United States; Division of Endocrinology, Diabetes and Hypertension, Department of Medicine, Brigham and Women’s Hospital, Boston, United States; Harvard Program in Neuroscience, Boston, United StatesInactivating mutations in the melanocortin 4 receptor (MC4R) gene cause monogenic obesity. Interestingly, female patients also display various degrees of reproductive disorders, in line with the subfertile phenotype of Mc4r KO female mice. However, the cellular mechanisms by which MC4R regulates reproduction are unknown. Kiss1 neurons directly stimulate gonadotropin-releasing hormone (GnRH) release through two distinct populations: the Kiss1ARH neurons, controlling GnRH pulses, and the sexually dimorphic Kiss1AVPV/PeN neurons controlling the preovulatory luteinizing hormone (LH) surge. Here, we show that Mc4r expressed in Kiss1 neurons regulates fertility in females. In vivo, deletion of Mc4r from Kiss1 neurons in female mice replicates the reproductive impairments of Mc4r KO mice without inducing obesity. Conversely, re-insertion of Mc4r in Kiss1 neurons of Mc4r null mice restores estrous cyclicity and LH pulsatility without reducing their obese phenotype. In vitro, we dissect the specific action of Mc4r on Kiss1ARH versus Kiss1AVPV/PeN neurons and show that Mc4r activation excites Kiss1ARH neurons through direct synaptic actions. In contrast, Kiss1AVPV/PeN neurons are normally inhibited by MC4R activation except under elevated estradiol levels, thus facilitating the activation of Kiss1AVPV/PeN neurons to induce the LH surge driving ovulation in females. Our findings demonstrate that POMCARH neurons acting through MC4R directly regulate reproductive function in females by stimulating the ‘pulse generator’ activity of Kiss1ARH neurons and restricting the activation of Kiss1AVPV/PeN neurons to the time of the estradiol-dependent LH surge, and thus unveil a novel pathway of the metabolic regulation of fertility by the melanocortin system.https://elifesciences.org/articles/100722kisspeptinmelanocortinPOMCreproduction |
| spellingShingle | Rajae Talbi Todd L Stincic Kaitlin Ferrari Choi Ji Hae Karol Walec Elizabeth Medve Achi Gerutshang Silvia Leon Elizabeth A McCarthy Oline K Rønnekleiv Martin J Kelly Victor M Navarro POMC neurons control fertility through differential signaling of MC4R in kisspeptin neurons eLife kisspeptin melanocortin POMC reproduction |
| title | POMC neurons control fertility through differential signaling of MC4R in kisspeptin neurons |
| title_full | POMC neurons control fertility through differential signaling of MC4R in kisspeptin neurons |
| title_fullStr | POMC neurons control fertility through differential signaling of MC4R in kisspeptin neurons |
| title_full_unstemmed | POMC neurons control fertility through differential signaling of MC4R in kisspeptin neurons |
| title_short | POMC neurons control fertility through differential signaling of MC4R in kisspeptin neurons |
| title_sort | pomc neurons control fertility through differential signaling of mc4r in kisspeptin neurons |
| topic | kisspeptin melanocortin POMC reproduction |
| url | https://elifesciences.org/articles/100722 |
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