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

IntroductionThe objective of this study was to assess basal insulin persistence, associated factors, and economic outcomes for insulin-naïve people with type 2 diabetes mellitus (T2DM) in Japan.MethodsPeople aged at least 18 years with T2DM with first claim for basal insulin between May 2006 and April 2013 (index date), no insulin use before index date, and continuous insurance coverage for 6 months before (baseline) and 12 months after index date were selected from the Japan Medical Center Database. On the basis of whether there were at least 30-day gaps in basal insulin treatment, patients were classified as continuers (no gap), interrupters (at least one prescription after gap), and discontinuers (no prescription after gap). A multinomial logistic regression model identified factors associated with persistence. Annual healthcare resource use and costs in the year after initiation were compared between continuers and interrupters and between continuers and discontinuers using propensity score-based inverse probability weighting to adjust for baseline differences.ResultsOf the 827 people included (mean age 50 years, ca. 71% male), 36% continued, 42% interrupted, and 22% discontinued basal insulin therapy in the year after initiation. Having at least one inpatient visit and using fewer classes of non-insulin antihyperglycemic medications during baseline were associated with lower likelihoods of continuing therapy. Relative to interrupters and discontinuers, continuers had lower hospitalization rates [continuers, 12.7%; interrupters, 25.4% (p < 0.001); discontinuers, 28.4% (p < 0.001)] and lower inpatient costs [continuers, ¥132,013; interrupters, ¥225,745 (p = 0.054); discontinuers, ¥320,582 (p = 0.036)], but higher pharmacy costs [continuers, ¥158,403; interrupters, ¥134,301 (p = 0.039); discontinuers, ¥121,593 (p = 0.002)] in the year after insulin initiation. Total healthcare costs were similar for the three cohorts.ConclusionsSubstantial proportions of people with T2DM in Japan interrupt or discontinue basal insulin within the year after initiation, and they have higher rates and costs of hospitalizations than patients who continue with their insulin therapy. Further research is needed to understand reasons behind basal insulin persistence and the implications thereof to help clinicians manage T2DM more effectively.FundingEli Lilly and Company, Boehringer Ingelheim.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-016-0215-6) contains supplementary material, which is available to authorized users.

a b s t r a c tBone is a highly vascularized organ, thus angiogenesis is a vital process during bone remodeling. However, the role of vascular systems in bone remodeling is not well recognized. Here we show that netrin-4 inhibits osteoclast differentiation in vitro and in vivo. Co-cultures of bone marrow macrophages with vascular endothelial cells markedly inhibited osteoclast differentiation. Adding a neutralizing antibody, or RNA interference against netrin-4, restored in vitro osteoclast differentiation. Administration of netrin-4 prevented bone loss in an osteoporosis mouse model by decreasing the osteoclast number. We propose that vascular endothelial cells interact with bone in suppressing bone through netrin-4.

From our previous studies, several protein tyrosine phosphatases (PTPase) are implicated in the early events leading to in vitro differentiation of both mouse erythroleukemia (MEL) and embryonal carcinoma (F9) cells. Among the PTPases, recent experiments suggest that a new PTPase (RIP) plays a critical role in differentiation processes, particularly at their early stages. We isolated eDNA clones for RIP from a RNA preparation isolated from differentiating MEL cells, and determined the total 7932 hp base sequence for RIP cDNA. The cDNA codes for a putative 269.8 kDa (2450 amino acids) protein with a PTPase catalytic domain. We have demonstrated that the transcripts exist in multiple forms, and among mouse tissues they were found predominantly in kidney and, to a lesser extent, in lung, heart, brain and testis. The RIP gene was mapped between D5MitgO and DSMit25 on mouse chromosome 5.

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