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PubMed: 0013-7227

The Developmental Increase in Adrenocortical 17,20-Lyase Activity (Biochemical Adrenarche) is Driven Primarily by Increasing Cytochrome b5 in Neonatal Rhesus Macaques.
Nguyen AD, Corbin CJ, Pattison JC, Bird IM, Conley AJ Related Articles The Developmental Increase in Adrenocortical 17,20-Lyase Activity (Biochemical Adrenarche) is Driven Primarily by Increasing Cytochrome b5 in Neonatal Rhesus Macaques. Endocrinology. 2008 Nov 26; Authors: Nguyen AD, Corbin CJ, Pattison JC, Bird IM, Conley AJ Adrenarche is thought to be experienced only by humans and some Old World primates despite observed regression of an adrenal fetal zone (FZ) and establishment of a functional zona reticularis (ZR) in other species like rhesus macaques. Adrenal differentiation remains poorly defined biochemically in non-human primates. The present studies defined ZR development in the neonatal rhesus by examining androgen synthetic capacity and factors affecting it in rhesus and marmoset adrenals. Western immunoblots examined expression of 17alpha-hydroxylase/17,20-lyase cytochrome P450 (P450c17), cytochrome b5 (b5), and 3beta-hydroxysteroid dehydrogenase (3betaHSD), among other key enzymes. 17,20-lyase activity was quantified in adrenal microsomes, as was the contribution of b5 to 17,20-lyase activity in microsomes and cell transfection experiments with rhesus and marmoset P450c17. Expression of b5 increased from birth to 3 months and was positively correlated with age and 17,20-lyase activity in the rhesus. Recombinant b5 addition stimulated 17,20-lyase activity to an extent inversely proportional to endogenous levels in adrenal microsomes. Although 3betaHSD expression also increased with age, P450c17, 21-hydroxylase cytochrome P450 and the redox partner, NADPH-cytochrome P450 oxidoreductase (CPR) did not; nor did recombinant CPR augment 17,20-lyase activity. Co-transfection with b5 induced a dose-dependent increase in DHEA synthesis by both non-human primate P450c17 enzymes. We conclude that the increase in 17,20-lyase activity characteristic of an adrenarche in rhesus macaques is driven primarily by increased b5 expression, without the need for a decrease in 3betaHSD, as suggested from human studies. The rhesus macaque is a relevant and accessible model for human ZR development and adrenal function. PMID: 19036885 [PubMed - as supplied by publisher]
An Extensive Genetic Program Occurring during Postnatal Growth in Multiple Tissues.
Finkielstain GP, Forcinito P, Lui JC, Barnes KM, Marino R, Makaroun S, Nguyen V, Lazarus JE, Nilsson O, Baron J Related Articles An Extensive Genetic Program Occurring during Postnatal Growth in Multiple Tissues. Endocrinology. 2008 Nov 26; Authors: Finkielstain GP, Forcinito P, Lui JC, Barnes KM, Marino R, Makaroun S, Nguyen V, Lazarus JE, Nilsson O, Baron J Mammalian somatic growth is rapid in early postnatal life but then slows and eventually ceases in multiple tissues. We hypothesized that there exists a postnatal gene expression program that is common to multiple tissues and is responsible for this coordinate growth deceleration. Consistent with this hypothesis, microarray analysis identified >1600 genes that were regulated with age (1 versus 4 weeks) coordinately in kidney, lung, and heart of male mice, including many genes that regulate proliferation. As examples, we focused on three growth-promoting genes, Igf2, Mest, and Peg3, that were markedly downregulated with age. In situ hybridization revealed that expression occurred in organ-specific parenchymal cells and that the decreasing expression with age was due to decreased expression per cell rather than a decreased number of expressing cells. The declining expression of these genes was slowed during hypothyroidism and growth inhibition (induced by propylthiouracil at 0-5 weeks of age) in male rats, suggesting that the normal decline in expression is driven by growth rather than by age per se. We conclude that there exists an extensive genetic program occurring during postnatal life. Many of the involved genes are regulated coordinately in multiple organs, including many genes that regulate cell proliferation. At least some of these are themselves apparently regulated by growth, suggesting that, in the embryo, a gene expression pattern is established that allows for rapid somatic growth of multiple tissues but then, during postnatal life, this growth leads to negative-feedback changes in gene expression that in turn slow and eventually halt somatic growth, thus imposing a fundamental limit on adult body size. PMID: 19036884 [PubMed - as supplied by publisher]
Type 2 deiodinase expression is induced by PPAR-{gamma} agonists in skeletal myocytes.
Grozovsky R, Ribich S, Rosene ML, Mulcahey MA, Huang SA, Patti ME, Bianco AC, Kim BW Related Articles Type 2 deiodinase expression is induced by PPAR-{gamma} agonists in skeletal myocytes. Endocrinology. 2008 Nov 26; Authors: Grozovsky R, Ribich S, Rosene ML, Mulcahey MA, Huang SA, Patti ME, Bianco AC, Kim BW The thyroid hormone activating type 2 deiodinase (D2) is known to play a role in brown adipose tissue mediated adaptive thermogenesis in rodents, but the finding of D2 in skeletal muscle raises the possibility of a broader metabolic role. In the current study, we examined the regulation of the D2 pathway in primary skeletal muscle myoblasts taken from both humans and mice. We found that pioglitazone treatment led to a 1.6 to 1.9-fold increase in primary human skeletal myocyte D2 activity; this effect was seen with other PPAR-gamma agonists. D2 activity in primary murine skeletal myotubes increased 2.8 fold in response to 5uM pioglitazone and 1.6 fold in response to 5nM insulin, and increased in a dose-dependent manner in response to lithocholic acid (maximum response at 25microM was approximately 3.8 fold). We compared Akt phosphorylation in primary myotubes derived from wild type and D2 knock-out mice: phospho-Akt was reduced by 50% in the D2KO muscle following 1nM insulin exposure. Expression of T3-responsive muscle genes via RT-qPCR suggests that D2KO cells have decreased thyroid hormone signaling, which could contribute to the abnormalities in insulin signaling. D2 activity in skeletal muscle fragments from both murine and human sources was low, on the order of approximately 0.01 fmol/min/mg of muscle protein. The phenotypic changes seen with D2KO cells support a metabolic role for D2 in muscle, hinting at a D2-mediated linkage between thyroid hormone and insulin signaling, but the low activity calls into question whether skeletal muscle D2 is a major source of plasma T3. PMID: 19036883 [PubMed - as supplied by publisher]
Prolactin receptor is required for normal glucose homeostasis and modulation of {beta}-cell mass during pregnancy.
Huang C, Snider F, Cross JC Related Articles Prolactin receptor is required for normal glucose homeostasis and modulation of {beta}-cell mass during pregnancy. Endocrinology. 2008 Nov 26; Authors: Huang C, Snider F, Cross JC Increased islet mass is an adaptive mechanism which occurs to combat insulin resistance during pregnancy. Prolactin (PRL) can enhance beta-cell proliferation and insulin secretion in vitro yet whether it is PRL or other pregnancy-related factors that mediate these adaptive changes during pregnancy is unknown. The objective of this study was to determine whether prolactin receptor (Prlr) is required for normal maternal glucose homeostasis during pregnancy. Intraperitoneal glucose tolerance test was performed on timed-pregnant Prlr(+/+) and heterozygous null Prlr(+/-) mice on days 0, 15, and 18 of pregnancy. Compared with Prlr(+/+) mice, Prlr(+/-) mice had impaired glucose clearance, decreased glucose-stimulated insulin release, higher non-fasted blood glucose and lower insulin levels during but not before pregnancy. There was no difference in their insulin tolerance. Prlr(+/+) mice show a significant incremental increase in islet density, beta-cell number and mass throughout pregnancy, which was attenuated in the Prlr(+/-) mice. Prlr(+/+) mice also had a more robust beta-cell proliferation rate during pregnancy, while there was no difference in apoptosis rate between the Prlr(+/+) and Prlr(+/-) mice before, during, or after pregnancy. Interestingly, genotype of the mothers had a significant impact on the offspring's phenotype, such that daughters derived from Prlr(+/-) mothers had a more severe phenotype than those derived from Prlr(+/+) mothers. In conclusion, this is the first in vivo demonstration that the action of pregnancy hormones, acting through Prlr, is required for normal maternal glucose tolerance during pregnancy by increasing beta-cell mass. PMID: 19036882 [PubMed - as supplied by publisher]
Role of c-Myb during PRL-induced Stat5a signaling in breast cancer cells.
Fang F, Rycyzyn MA, Clevenger CV Related Articles Role of c-Myb during PRL-induced Stat5a signaling in breast cancer cells. Endocrinology. 2008 Nov 26; Authors: Fang F, Rycyzyn MA, Clevenger CV Implicated in the pathogenesis of breast cancer, prolactin (PRL) mediates its function in part through the prolactin receptor (PRLr)-associated Jak2/Stat5 signaling complex. To delineate the mechanisms of Stat5a regulation in breast cancer, transcription factor-transcription factor (TF-TF) array analysis was employed to identify associated transcriptional regulators. These analyses revealed a PRL-inducible association of Stat5a with the transcription factor and proto-oncogene c-Myb. Confirmatory co-immunoprecipitation studies using lysates from both T47D and MCF7 breast cancer cells revealed an PRL-inducible association between these transcription factors. Ectopic expression of c-Myb enhanced the PRL-induced expression from both composite and synthetic Stat5a-responsive luciferase reporters. Chromatin immunoprecipitation (ChIP) assays also revealed a PRL-inducible association between c-Myb and endogenous Stat5a-responsive CISH promoter, which was associated with an enhanced expression of CISH gene product at the RNA and protein levels. SiRNA-mediated c-Myb knockdown impaired the PRL-induced mRNA expression of five Stat5-responsive genes. DNA binding-defective mutants of c-Myb, incapable of activating expression from a c-Myb-responsive reporter, maintained their ability to enhance a Stat5a-responsive reporter. At a cellular level, ectopic expression of c-Myb resulted in an increase in T47D proliferation. Taken together, these results indicate that c-Myb potentiates Stat5a-driven gene expression, possibly functioning as a Stat5a co-activator, in human breast cancer. PMID: 19036881 [PubMed - as supplied by publisher]
HEXOSAMINE BIOSYNTHESIS PATHWAY FLUX CONTRIBUTES TO INSULIN RESISTANCE VIA ALTERING MEMBRANE PIP2 AND CORTICAL F-ACTIN.
Bhonagiri P, Pattar GR, Horvath EM, Habegger KM, McCarthy AM, Elmendorf JS Related Articles HEXOSAMINE BIOSYNTHESIS PATHWAY FLUX CONTRIBUTES TO INSULIN RESISTANCE VIA ALTERING MEMBRANE PIP2 AND CORTICAL F-ACTIN. Endocrinology. 2008 Nov 26; Authors: Bhonagiri P, Pattar GR, Horvath EM, Habegger KM, McCarthy AM, Elmendorf JS We recently found that plasma membrane (PM) phosphatidylinositol 4,5 bisphosphate (PIP2)-regulated filamentous actin (F-actin) polymerization was diminished in hyperinsulinemic cell culture models of insulin resistance. Here we delineated if increased glucose flux through the hexosamine biosynthesis pathway (HBP) causes the PIP2/F-actin dysregulation and insulin resistance induced by hyperinsulinemia. Increased HBP activity was detected in 3T3-L1 adipocytes cultured under conditions closely resembling physiological hyperinsulinemia (5 nM Ins; 12 h) and in cells where HBP activity was amplified by 2 mM glucosamine (GlcN). Both the physiological hyperinsulinemia and experimental GlcN challenge induced comparable losses of PIP2 and F-actin. In addition to protecting against the insulin-induced membrane/cytoskeletal abnormality and insulin-resistant state, exogenous PIP2 corrected the GlcN-induced insult on these parameters. Moreover, in accordance with HBP flux directly weakening PIP2/F-actin structure, inhibition of the rate-limiting HBP enzyme (GFAT, glutamine:fructose-6-phosphate amidotransferase) restored PIP2-regulated F-actin structure and insulin responsiveness. Conversely, overexpression of GFAT was associated with a loss of detectable PM PIP2 and insulin sensitivity. A slight decrease in intracellular ATP resulted from amplifying HBP by hyperinsulinemia and GlcN. However, experimental maintenance of the intracellular ATP pool under both conditions with inosine did not reverse the PIP2/F-actin-based insulin-resistant state. Furthermore, less invasive challenges with glucose, in the absence of insulin, also led to PIP2/F-actin dysregulation. Accordingly, we suggest that the functionality of cell systems dependent on PIP2 and/or F-actin status, such as the glucose transport system, can be critically compromised by inappropriate HBP activity. PMID: 19036880 [PubMed - as supplied by publisher]

PubMed: 0804-4643

Identification of novel mutations of the WFS1 gene in Brazilian patients with Wolfram syndrome.
Gasparin MR, Crispim F, Paula S, Freire MB, Dalbosco I, Della Manna T, Salles JE, Gasparin F, Guedes A, Marcantonio J, Gambini M, Salim C, Moisés R Related Articles Identification of novel mutations of the WFS1 gene in Brazilian patients with Wolfram syndrome. Eur J Endocrinol. 2008 Nov 28; Authors: Gasparin MR, Crispim F, Paula S, Freire MB, Dalbosco I, Della Manna T, Salles JE, Gasparin F, Guedes A, Marcantonio J, Gambini M, Salim C, Moisés R Objective: Wolfram syndrome (WS) is a rare, progressive, neurodegenerative disorder with an autosomal recessive pattern of inheritance. The gene for WS, WFS1, was identified on chromosome 4p16 and most WS patients carry mutations in this gene. However, some studies have provided evidence for genetic heterogeneity and the genotype-phenotype relationships are not clear. Our aim was to ascertain the spectrum of WFS1 mutations in Brazilian patients with Wolfram syndrome and to examine the phenotype-genotype relationships in these patients. Design and Methods: Clinical characterization and analyses of the WFS1 gene were performed in 27 Brazilian patients with Wolfram syndrome from 19 families. Results: We identified 15 different mutations in the WFS1 gene in 26 patients, among which 9 are novel. All mutations occurred in exon 8, except for one missense mutation which was located in exon 5. Although, we did not find any clear phenotype-genotype relationship in patients with mutations in exon 8, the homozygous missense mutation in exon 5 was associated with a mild phenotype: onset of diabetes mellitus and optic atrophy during adulthood with good metabolic control being achieved with low doses of sulfonylurea. Conclusions: Our data show that WFS1 is the major gene involved in WS in Brazilian patients and most mutations are concentrated in exon 8. Also, our study increases the spectrum of WFS1 mutations. Although no clear phenotype-genotype relationship was found for mutations in exon 8, a mild phenotype was associated with a homozygous missense mutation in exon 5. PMID: 19042979 [PubMed - as supplied by publisher]
Postoperative mortality in parathyroid surgery in Sweden during five decades, improved outcome despite older patients.
Norenstedt S, Ekbom A, Brandt L, Zedenius J, Nilsson IL Related Articles Postoperative mortality in parathyroid surgery in Sweden during five decades, improved outcome despite older patients. Eur J Endocrinol. 2008 Nov 28; Authors: Norenstedt S, Ekbom A, Brandt L, Zedenius J, Nilsson IL Objective Primary hyperparathyroidism (pHPT) is a common endocrine disorder. In Europe, pHPT has been associated with premature death in cardiovascular disorders. Our question was whether the risk of postoperative death has been affected by the increased proportion of elderly patients referred for parathyroid surgery. Methods The nationwide Cancer Registry and Causes-of-Death Registry were used to analyse mortality among 14,635 Swedish patients subjected to parathyroid adenomectomy during 1961 to 2004. Standard mortality ratios (SMR) and the 95% confidence intervals (CI) were calculated with the entire Swedish population as control, standardized for age, gender and calendar year. Results The observation period was more than 166,000 person years. The overall perioperative (30-day) mortality rate was 1.3% (185/14,635; SMR 7.9; CI 6.82 - 9.15); 1.1% for women (132/11,500; SMR 7.56; CI 6.32-8.96) and 1.7% for men (53/3,135; SMR 9.01; CI 6.75-11.78). Cardiovascular disorder was the dominant cause of death in both sexes and in all the investigated age groups (age 15-54yr SMR 29.0; CI 9.42 -67.71, age 55-74yr SMR 6.12; CI 3.96 - 9.03, age 75- SMR 5.26; CI 3.74 - 7.19). The SMR decreased over the calendar year period notwithstanding a rising proportion of elderly individuals. In the most recent period, 1997-2004, the perioperative mortality rate was only 0.5%, which represents a normalisation of the excess mortality risk during the first post-PTx year (SMR 1.17; CI 0.92 - 1.46). Conclusion Parathyroid adenomectomy is a safe procedure, regardless of patient age. PMID: 19042978 [PubMed - as supplied by publisher]

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