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.adrenocorticotropic hormone (ACTH) ͉ familial glucocorticoid deficiency (FGD) ͉ hypothalamus-pituitary-adrenal ͉ zona fasciculata T he adrenal gland regulates a number of essential physiological functions in adult organisms through the production of steroids and catecholamines. Maintenance of adrenal structure and function is regulated through the integration of extra-and intracellular signals. The pituitary hormone ACTH (i.e., adrenocorticotropic hormone), which is derived from the proopiomelanocortin (POMC) polypeptide precursor, is the principal regulator that stimulates adrenal glucocorticoid (GC) biosynthesis and secretion via the membrane-bound specific receptor for ACTH, ACTH receptor/melanocortin 2 receptor (MC2R) (1).It was previously demonstrated that, although POMC knockout (KO) mice are born at the expected Mendelian frequency, three-quarters of POMC KO mice undergo neonatal death. Furthermore, those mice surviving to adulthood exhibit obesity, pigmentation defects, and adrenal insufficiency (2-4). POMC KO mice possess macroscopically detectable adrenal glands that lack normal architecture (2, 4, 5). These results demonstrate the importance of POMC-derived peptides in regulating the hypothalamus-pituitary-adrenal axis and adrenal development.Familial glucocorticoid deficiency (FGD), or hereditary unresponsiveness to ACTH [Online Mendelian Inheritance in Man (OMIM) no. 202200; www.ncbi.nlm.nih.gov/entrez/dispomim.cgi?idϭ202200], is an autosomal recessive disorder ...

Proinflammatory cytokines including interleukin (IL)-1 and IL-6 exert pleiotropic effects on the neuro-immunoendocrine system. Previously, we showed that IL-1 receptor antagonist-deficient (IL-1Ra ؊/؊ ) mice show a lean phenotype due to an abnormal lipid metabolism. On the contrary, it was reported that IL-6 ؊/؊ mice exhibit obesity after 6 months of age. This study sought to assess the roles of IL-1 and IL-6 in body weight homeostasis. We generated mice deficient in IL-6 and IL-1Ra (IL-6 ؊/؊ IL-1Ra

a b s t r a c tRecent studies have indicated that acetylcholine (ACh) plays a vital role in various tissues, while the role of ACh in bone metabolism remains unclear. Here we demonstrated that ACh induced cell proliferation and reduced alkaline phosphatase (ALP) activity via nicotinic (nAChRs) and muscarinic acetylcholine receptors (mAChRs) in osteoblasts. We detected mRNA expression of several nAChRs and mAChRs. Furthermore, we showed that cholinergic components were up-regulated and subunits/subtypes of acetylcholine receptors altered during osteoblast differentiation. To our knowledge, this is the first report demonstrating that osteoblasts express specific acetylcholine receptors and cholinergic components and that ACh plays a possible role in regulating the proliferation and differentiation of osteoblasts. Crown