Melanocortin 2 receptor is required for adrenal gland development, steroidogenesis, and neonatal gluconeogenesis.
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.
Chida
Dai
D
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
Nakagawa
Shinichi
S
Nagai
So
S
Sagara
Hiroshi
H
Katsumata
Harumi
H
Imaki
Toshihiro
T
Suzuki
Harumi
H
Mitani
Fumiko
F
Ogishima
Tadashi
T
Shimizu
Chikara
C
Kotaki
Hayato
H
Kakuta
Shigeru
S
Sudo
Katsuko
K
Koike
Takao
T
Kubo
Mitsumasa
M
Iwakura
Yoichiro
Y
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*
D044103:Receptor, Melanocortin, Type 2; D013256:Steroids