Melanocortin 2 receptor is required for adrenal gland development, steroidogenesis, and neonatal gluconeogenesis

Dai Chida, Shinichi Nakagawa, So Nagai, Hiroshi Sagara, Harumi Katsumata, Toshihiro Imaki, Harumi Suzuki, Fumiko Mitani, Tadashi Ogishima, Chikara Shimizu, Hayato Kotaki, Shigeru Kakuta, Katsuko Sudo, Takao Koike, Mitsumasa Kubo, Yoichiro Iwakura

Research output: Contribution to journalArticle

91 Citations (Scopus)

Abstract

ACTH (i.e., corticotropin) is the principal regulator of the hypothalamus-pituitary-adrenal axis and stimulates steroidogenesis in the adrenal gland via the specific cell-surface melanocortin 2 receptor (MC2R). Here, we generated mice with an inactivation mutation of the MC2R gene to elucidate the roles of MC2R in adrenal development, steroidogenesis, and carbohydrate metabolism. These mice, the last of the knockout (KO) mice to be generated for melanocortin family receptors, provide the opportunity to compare the phenotype of proopiomelanocortin KO mice with that of MC1R-MC5R KO mice. We found that the MC2R KO mutation led to neonatal lethality in three-quarters of the mice, possibly as a result of hypoglycemia. Those surviving to adulthood exhibited macroscopically detectable adrenal glands with markedly atrophied zona fasciculata, whereas the zona glomerulosa and the medulla remained fairly intact. Mutations of MC2R have been reported to be responsible for 25% of familial glucocorticoid deficiency (FGD) cases. Adult MC2R KO mice resembled FGD patients in several aspects, such as undetectable levels of corticosterone despite high levels of ACTH, unresponsiveness to ACTH, and hypoglycemia after prolonged (36 h) fasting. However, MC2R KO mice differ from patients with MC2R-null mutations in several aspects, such as low aldosterone levels and unaltered body length. These results indicate that MC2R is required for postnatal adrenal development and adrenal steroidogenesis and that MC2R KO mice provide a useful animal model by which to study FGD.

Original languageEnglish
Pages (from-to)18205-18210
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number46
DOIs
Publication statusPublished - Nov 13 2007

Fingerprint

Receptor, Melanocortin, Type 2
Gluconeogenesis
Adrenal Glands
Knockout Mice
Adrenocorticotropic Hormone
Glucocorticoids
Mutation
Hypoglycemia
Melanocortin Receptors
Zona Fasciculata
Zona Glomerulosa
Pro-Opiomelanocortin
Carbohydrate Metabolism
Corticosterone
Aldosterone
Hypothalamus

All Science Journal Classification (ASJC) codes

  • General

Cite this

Melanocortin 2 receptor is required for adrenal gland development, steroidogenesis, and neonatal gluconeogenesis. / Chida, Dai; Nakagawa, Shinichi; Nagai, So; Sagara, Hiroshi; Katsumata, Harumi; Imaki, Toshihiro; Suzuki, Harumi; Mitani, Fumiko; Ogishima, Tadashi; Shimizu, Chikara; Kotaki, Hayato; Kakuta, Shigeru; Sudo, Katsuko; Koike, Takao; Kubo, Mitsumasa; Iwakura, Yoichiro.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 104, No. 46, 13.11.2007, p. 18205-18210.

Research output: Contribution to journalArticle

Chida, D, Nakagawa, S, Nagai, S, Sagara, H, Katsumata, H, Imaki, T, Suzuki, H, Mitani, F, Ogishima, T, Shimizu, C, Kotaki, H, Kakuta, S, Sudo, K, Koike, T, Kubo, M & Iwakura, Y 2007, 'Melanocortin 2 receptor is required for adrenal gland development, steroidogenesis, and neonatal gluconeogenesis', Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 46, pp. 18205-18210. https://doi.org/10.1073/pnas.0706953104
Chida, Dai ; Nakagawa, Shinichi ; Nagai, So ; Sagara, Hiroshi ; Katsumata, Harumi ; Imaki, Toshihiro ; Suzuki, Harumi ; Mitani, Fumiko ; Ogishima, Tadashi ; Shimizu, Chikara ; Kotaki, Hayato ; Kakuta, Shigeru ; Sudo, Katsuko ; Koike, Takao ; Kubo, Mitsumasa ; Iwakura, Yoichiro. / Melanocortin 2 receptor is required for adrenal gland development, steroidogenesis, and neonatal gluconeogenesis. In: Proceedings of the National Academy of Sciences of the United States of America. 2007 ; Vol. 104, No. 46. pp. 18205-18210.
@article{416042368c3c4f7c944cb5a24cf2138d,
title = "Melanocortin 2 receptor is required for adrenal gland development, steroidogenesis, and neonatal gluconeogenesis",
abstract = "ACTH (i.e., corticotropin) is the principal regulator of the hypothalamus-pituitary-adrenal axis and stimulates steroidogenesis in the adrenal gland via the specific cell-surface melanocortin 2 receptor (MC2R). Here, we generated mice with an inactivation mutation of the MC2R gene to elucidate the roles of MC2R in adrenal development, steroidogenesis, and carbohydrate metabolism. These mice, the last of the knockout (KO) mice to be generated for melanocortin family receptors, provide the opportunity to compare the phenotype of proopiomelanocortin KO mice with that of MC1R-MC5R KO mice. We found that the MC2R KO mutation led to neonatal lethality in three-quarters of the mice, possibly as a result of hypoglycemia. Those surviving to adulthood exhibited macroscopically detectable adrenal glands with markedly atrophied zona fasciculata, whereas the zona glomerulosa and the medulla remained fairly intact. Mutations of MC2R have been reported to be responsible for 25{\%} of familial glucocorticoid deficiency (FGD) cases. Adult MC2R KO mice resembled FGD patients in several aspects, such as undetectable levels of corticosterone despite high levels of ACTH, unresponsiveness to ACTH, and hypoglycemia after prolonged (36 h) fasting. However, MC2R KO mice differ from patients with MC2R-null mutations in several aspects, such as low aldosterone levels and unaltered body length. These results indicate that MC2R is required for postnatal adrenal development and adrenal steroidogenesis and that MC2R KO mice provide a useful animal model by which to study FGD.",
author = "Dai Chida and Shinichi Nakagawa and So Nagai and Hiroshi Sagara and Harumi Katsumata and Toshihiro Imaki and Harumi Suzuki and Fumiko Mitani and Tadashi Ogishima and Chikara Shimizu and Hayato Kotaki and Shigeru Kakuta and Katsuko Sudo and Takao Koike and Mitsumasa Kubo and Yoichiro Iwakura",
year = "2007",
month = "11",
day = "13",
doi = "10.1073/pnas.0706953104",
language = "English",
volume = "104",
pages = "18205--18210",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "46",

}

TY - JOUR

T1 - Melanocortin 2 receptor is required for adrenal gland development, steroidogenesis, and neonatal gluconeogenesis

AU - Chida, Dai

AU - Nakagawa, Shinichi

AU - Nagai, So

AU - Sagara, Hiroshi

AU - Katsumata, Harumi

AU - Imaki, Toshihiro

AU - Suzuki, Harumi

AU - Mitani, Fumiko

AU - Ogishima, Tadashi

AU - Shimizu, Chikara

AU - Kotaki, Hayato

AU - Kakuta, Shigeru

AU - Sudo, Katsuko

AU - Koike, Takao

AU - Kubo, Mitsumasa

AU - Iwakura, Yoichiro

PY - 2007/11/13

Y1 - 2007/11/13

N2 - ACTH (i.e., corticotropin) is the principal regulator of the hypothalamus-pituitary-adrenal axis and stimulates steroidogenesis in the adrenal gland via the specific cell-surface melanocortin 2 receptor (MC2R). Here, we generated mice with an inactivation mutation of the MC2R gene to elucidate the roles of MC2R in adrenal development, steroidogenesis, and carbohydrate metabolism. These mice, the last of the knockout (KO) mice to be generated for melanocortin family receptors, provide the opportunity to compare the phenotype of proopiomelanocortin KO mice with that of MC1R-MC5R KO mice. We found that the MC2R KO mutation led to neonatal lethality in three-quarters of the mice, possibly as a result of hypoglycemia. Those surviving to adulthood exhibited macroscopically detectable adrenal glands with markedly atrophied zona fasciculata, whereas the zona glomerulosa and the medulla remained fairly intact. Mutations of MC2R have been reported to be responsible for 25% of familial glucocorticoid deficiency (FGD) cases. Adult MC2R KO mice resembled FGD patients in several aspects, such as undetectable levels of corticosterone despite high levels of ACTH, unresponsiveness to ACTH, and hypoglycemia after prolonged (36 h) fasting. However, MC2R KO mice differ from patients with MC2R-null mutations in several aspects, such as low aldosterone levels and unaltered body length. These results indicate that MC2R is required for postnatal adrenal development and adrenal steroidogenesis and that MC2R KO mice provide a useful animal model by which to study FGD.

AB - ACTH (i.e., corticotropin) is the principal regulator of the hypothalamus-pituitary-adrenal axis and stimulates steroidogenesis in the adrenal gland via the specific cell-surface melanocortin 2 receptor (MC2R). Here, we generated mice with an inactivation mutation of the MC2R gene to elucidate the roles of MC2R in adrenal development, steroidogenesis, and carbohydrate metabolism. These mice, the last of the knockout (KO) mice to be generated for melanocortin family receptors, provide the opportunity to compare the phenotype of proopiomelanocortin KO mice with that of MC1R-MC5R KO mice. We found that the MC2R KO mutation led to neonatal lethality in three-quarters of the mice, possibly as a result of hypoglycemia. Those surviving to adulthood exhibited macroscopically detectable adrenal glands with markedly atrophied zona fasciculata, whereas the zona glomerulosa and the medulla remained fairly intact. Mutations of MC2R have been reported to be responsible for 25% of familial glucocorticoid deficiency (FGD) cases. Adult MC2R KO mice resembled FGD patients in several aspects, such as undetectable levels of corticosterone despite high levels of ACTH, unresponsiveness to ACTH, and hypoglycemia after prolonged (36 h) fasting. However, MC2R KO mice differ from patients with MC2R-null mutations in several aspects, such as low aldosterone levels and unaltered body length. These results indicate that MC2R is required for postnatal adrenal development and adrenal steroidogenesis and that MC2R KO mice provide a useful animal model by which to study FGD.

UR - http://www.scopus.com/inward/record.url?scp=36749073453&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=36749073453&partnerID=8YFLogxK

U2 - 10.1073/pnas.0706953104

DO - 10.1073/pnas.0706953104

M3 - Article

C2 - 17989225

AN - SCOPUS:36749073453

VL - 104

SP - 18205

EP - 18210

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 46

ER -