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M Quinkler, H Troeger, E Eigendorff, C Maser-Gluth, A Stiglic, W Oelkers, V Bahr, and S Diederich

The 11beta-hydroxysteroid dehydrogenases (11beta-HSDs) convert cortisol to its inactive metabolite cortisone and vice versa. 11beta-HSD type 1 (11beta-HSD-1) functions as a reductase in vivo, regulating intracellular cortisol levels and its access to the glucocorticoid receptor. In contrast, 11beta-HSD-2 only mediates oxidation of natural glucocorticoids, and protects the mineralocorticoid receptor from high cortisol concentrations. We investigated the in vivo and in vitro effects of ACTH on the recently characterized 11beta-HSDs in guinea pig liver and kidney. Tissue slices of untreated guinea pigs were incubated with (3)H-labelled cortisol or cortisone and ACTH(1-24) (10(-10) and 10(-9) mol/l). The 11beta-HSD activities in liver and kidney slices were not influenced by in vitro incubation with ACTH(1-24). In addition, guinea pigs were treated with ACTH(1-24) or saline injections s.c. for 3 days. Liver and kidney tissue slices of these animals were incubated with (3)H-labelled cortisol or cortisone. In vivo ACTH treatment significantly increased reductase and decreased oxidase activity in liver and kidney. Furthermore, 11beta-HSD-1 activity assessed by measurement of the urinary ratio of (tetrahydrocortisol (THF)+5alphaTHF)/(tetrahydrocortisone) was significantly increased after ACTH treatment compared with the control group. Plasma levels of cortisol, cortisone, progesterone, 17-hydroxyprogesterone and androstenedione increased significantly following in vivo ACTH treatment. The enhanced reductase activity of the hepatic and renal 11beta-HSD-1 is apparently caused by cortisol or other ACTH-dependent steroids rather than by ACTH itself. This may be an important fine regulation of the glucocorticoid tonus for stress adaptation in every organ, e.g. enhanced gluconeogenesis in liver.

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Zhen Yang, Chunming Guo, Ping Zhu, Wenjiao Li, Leslie Myatt, and Kang Sun

& Stewart 2005 ). There are two isozymes of 11β-HSD in the body ( Seckl 1993 , Draper & Stewart 2005 ). 11β-HSD1 is ubiquitously distributed in glucocorticoid (GC) target organs where it enhances the binding of cortisol to the relatively low-affinity GR by

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Darryl L Hadsell, Albert F Parlow, Daniel Torres, Jessy George, and Walter Olea

also be mediated through the actions of IGF-I ( Dehoff et al . 1988 , Prosser et al . 1990 ). In dairy cows, GH allows for milk production to maintain at higher levels for a longer period of time producing enhanced ‘lactation persistence’ ( Bauman

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RM Kimble, BH Breier, PD Gluckman, and JE Harding

Infants with upper gut atresia often have impaired intrauterine growth and gut function. IGF-I is important in fetal growth and is contained in amniotic fluid. We therefore wanted to test the hypothesis that IGF-I infused into fetal gut would reverse the effects of an upper gut obstruction on gut structure and growth in fetal sheep. At 90 days gestation fetuses (n=6 per group) underwent oesophageal ligation, followed by continuous infusion of IGF-I (1-8 microgram/day) or saline into the gut beyond the ligation until 137 days. Controls underwent sham ligation only. Oesophageal ligation tended to reduce fetal body and organ weights. IGF-I treatment prevented this reduction and increased body length and spleen weight above those of controls. The decrease in bowel wall thickness induced by oesophageal ligation was also prevented by IGF-I treatment. Amniotic fluid IGF-I concentrations did not change over gestation and were higher in the IGF-I treated group. No change in fetal plasma IGF-I concentrations were detectable. We conclude that enterally administered IGF-I may enhance fetal growth and gut development in utero and that IGF-I in amniotic fluid may play a physiological role in gut development in the fetus.

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Y Yang, J Cao, W Xiong, J Zhang, Q Zhou, H Wei, C Liang, J Deng, T Li, S Yang, L Xu, and L Xu

It has been documented that stress or glucocorticoids have conflicting effects on memory under different conditions. However, it is not fully understood why stress can either impair or enhance memory. Here, we have examined the performance of six age groups of Wistar rats in a water maze spatial task to evaluate the effects of stress under different conditions. We found that the impairment or enhancement effect of an 'elevated platform' (EP) stress on memory was dependent on previous stress experience and on age. EP stress impaired memory retrieval in water maze naive animals, but enhanced rather than impaired memory retrieval in young water maze stress-experienced animals. Furthermore, exogenously applied corticosterone or foot shock stress before water maze training prevented the impairment of memory retrieval that should be induced by treatment with corticosterone or foot shock before the 'probe trial'. Again, memory retrieval was enhanced in young animals under these conditions, and this enhancement can be prevented by the glucocorticoid receptor antagonist RU 38486. Thus, glucocorticoid receptor activation not only induced impairment of memory but also increased the capacity of young animals to overcome a later stress. The present findings suggest that the effect of stress on memory can be switched from impairment to enhancement dependent on both stress experience and age.

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R Vasilatos-Younken, Y Zhou, X Wang, JP McMurtry, RW Rosebrough, E Decuypere, N Buys, VM Darras, S Van Der Geyten, and F Tomas

In contrast to most vertebrates, GH reportedly has no effect upon somatic growth of the chicken. However, previous studies employed only one to two dosages of the hormone, and limited evidence exists of a hyperthyroid response that may confound its anabolic potential. This study evaluated the effects of 0, 10, 50, 100 and 200 microgram/kg body weight per day chicken GH (cGH) (0-200 GH) infused i.v. for 7 days in a pulsatile pattern to immature, growing broiler chickens (9-10 birds/dosage). Comprehensive profiles of thyroid hormone metabolism and measures of somatic growth were obtained. Overall (average) body weight gain was reduced 25% by GH, with a curvilinear, dose-dependent decrease in skeletal (breast) muscle mass that was maximal (12%) at 100 GH. This profile mirrored GH dose-dependent decreases in hepatic type III deiodinase (DIII) activity and increases in plasma tri-iodothyronine (T(3)), with bot! h also maximal (74 and 108% respectively) at 100 GH. No effect on type I deiodinase was observed. At the maximally effective dosage, hepatic DIII gene expression was reduced 44% versus controls. Despite dose-dependent, fold-increases in hepatic IGF-I protein content, circulating IGF-I was not altered with GH infusion, suggesting impairment of hepatic IGF-I release. Significant, GH dose-dependent increases in plasma non-esterified fatty acid and glucose, and overall decreases in triacylglycerides were also observed. At 200 GH, feed intake was significantly reduced (19%; P<0.05) versus controls; however, additional control birds pair-fed to this level did not exhibit any responses observed for GH-treated birds. The results of this study support a pathway by which GH impacts on thyroid hormone metabolism beginning at a pretranslational level, with reduced hepatic DIII gene expression, translating to reduced protein (enzyme) ex! pression, and reflected in a reduced level of peripheral T(3)-degrading activity. This contributes to decreased conversion of T(3) to its inactive form, thereby elevating circulating T(3) levels. The hyper-T(3) state leads to reduced net skeletal muscle deposition, and may impair release of GH-enhanced, hepatic IGF-I. In conclusion, GH has significant biological effects in the chicken, but profound metabolic actions predominate that may confound positive, IGF-I-mediated skeletal muscle growth.

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Melissa F Jackson, Dung Luong, Dor Dor Vang, Dilip K Garikipati, James B Stanton, O Lynne Nelson, and Buel D Rodgers

beneficial effects on obesity-related disorders, on preventing frailty, and on mitigating cardiovascular disease ( Winett et al . 2009 ). Thus, a better understanding of sarcopenia or mechanisms to enhance skeletal muscle mass could help to develop novel

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Lisa M Arendt, Lindsay C Evans, Debra E Rugowski, Maria Jose Garcia-Barchino, Hallgeir Rui, and Linda A Schuler

estrogenic signals in a variety of experimental systems: it increases ER expression ( Edery et al . 1985 , Frasor & Gibori 2003 , Gutzman et al . 2004 a ), and cooperatively activates the AP-1 transcriptional enhancer ( Gutzman et al . 2005 ). These

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Isabel R Orriss, Dilek Guneri, Mark O R Hajjawi, Kristy Shaw, Jessal J Patel, and Timothy R Arnett

-thioUTP (≥0.1 µM) dose-dependently increased extracellular ATP levels by up to 50% (F, G, H) but had no effect in P2Y 2 R −/− osteoclasts. Long-term treatment (7 days) with (I) UTP and (J) 2-thioUTP treatment enhanced ATP release by up to 70% and 65

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Sarit Ben-Shmuel, Eyal J Scheinman, Rola Rashed, Zila Shen Orr, Emily J Gallagher, Derek LeRoith, and Ran Rostoker

triglycerides levels in serum, were shown to have enhanced mammary tumor growth. Cholesterol-induced activation of the PI3K/Akt signaling pathway in tumor cells was suggested as the molecular mechanism linking hypercholesterolemia and tumor growth ( Alikhani et