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.
authors.affiliation: Division of Cell Biology, Center for Experimental Medicine, and Fine Morphology Laboratory, Department of Basic Medical Science, Institute of Medical Science, University of Tokyo, 4-6-1, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan. dchida@ri.imcj.go.jp
authors.forename: Dai
authors.initials: D
authors.lastname: Chida
authors.forename: Shinichi
authors.initials: S
authors.lastname: Nakagawa
authors.forename: So
authors.initials: S
authors.lastname: Nagai
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sagara
authors.forename: Harumi
authors.initials: H
authors.lastname: Katsumata
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Imaki
authors.forename: Harumi
authors.initials: H
authors.lastname: Suzuki
authors.forename: Fumiko
authors.initials: F
authors.lastname: Mitani
authors.forename: Tadashi
authors.initials: T
authors.lastname: Ogishima
authors.forename: Chikara
authors.initials: C
authors.lastname: Shimizu
authors.forename: Hayato
authors.initials: H
authors.lastname: Kotaki
authors.forename: Shigeru
authors.initials: S
authors.lastname: Kakuta
authors.forename: Katsuko
authors.initials: K
authors.lastname: Sudo
authors.forename: Takao
authors.initials: T
authors.lastname: Koike
authors.forename: Mitsumasa
authors.initials: M
authors.lastname: Kubo
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
mesh_terms: D000311:Adrenal Glands / Q000254:growth & development*; D000818:Animals; D000831:Animals, Newborn; D005943:Gluconeogenesis / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D044103:Receptor, Melanocortin, Type 2 / Q000235:genetics / Q000502:physiology*; D013256:Steroids / Q000096:biosynthesis*
chemical_list: D044103:Receptor, Melanocortin, Type 2; D013256:Steroids