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  • Abstract: Thyroid* x
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  • Abstract: Thyroglobulin x
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G J M Ferrier, A M Pierson, P M Jones, S R Bloom, S I Girgis and S Legon

ABSTRACT

We have used the polymerase chain reaction with mixed sequence primers to generate a probe for rat amylin and have used this to detect expression in various rat tissues. Amylin mRNA is found in greatest concentrations in the pancreas where a single mRNA species can be detected giving a hybridisation signal intensity approximately 10% that of insulin mRNA. When the beta cell population was depleted with streptozotocin, both amylin and insulin mRNAs were reduced to a similar extent. Consistent with its supposed role in the control of carbohydrate metabolism, amylin mRNA was also found in the stomach. Unlike the related peptide, CGRP, amylin mRNA is not present in the thyroid and is not widely distributed in the central nervous system. The only nervous tissue in which it could be detected was the dorsal root ganglion. Surprisingly, amylin mRNA was also found in the lung though only at very low levels.

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Amy Warner and Jens Mittag

It has long been known that thyroid hormone has profound direct effects on metabolism and cardiovascular function. More recently, it was shown that the hormone also modulates these systems by actions on the central autonomic control. Recent studies that either manipulated thyroid hormone signalling in anatomical areas of the brain or analysed seasonal models with an endogenous fluctuation in hypothalamic thyroid hormone levels revealed that the hormone controls energy turnover. However, most of these studies did not progress beyond the level of anatomical nuclei; thus, the neuronal substrates as well as the molecular mechanisms remain largely enigmatic. This review summarises the evidence for a role of thyroid hormone in the central autonomic control of peripheral homeostasis and advocates novel strategies to address thyroid hormone action in the brain on a cellular level.

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C Svensson

ABSTRACT

This study was undertaken to investigate the effects of growth hormone (GH) on the in vitro maturation of the metabolism of fetal rat islets. For this purpose fetal islets were obtained from 21-day-old fetuses by mild collagenase digestion of the pancreas and cultured in RPMI 1640 supplemented with 10% fetal calf serum. After one day the medium was changed and supplemented with 1% fetal calf serum with or without GH (1 μg/ml, human recombinant) and the islets cultured for another two days. Islets were then studied with regard to insulin secretion, (pro)insulin and total protein biosynthesis, glucose utilization and oxidation, thymidine incorporation, insulin and DNA contents and the contents of mRNAs for either insulin, adenine nucleotide translocator or cytochrome b. In addition, the activities of glucose phosphorylating enzymes and succinate-cytochrome c reductase were measured. Islets treated with GH showed increased insulin secretion in response to glucose, increased rates of glucose oxidation and utilization, increased thymidine incorporation and increased activities of succinate cytochrome c reductase and glucose phosphorylation at high glucose concentrations. There were, however, no changes in (pro)insulin and total protein biosynthesis, contents of insulin and DNA or the contents of any of the mRNAs. These combined data show that fetal β-cells are sensitive to growth hormone with respect to glucose metabolism, insulin release and DNA replication. The increased rates of islet glucose phosphorylation may reflect glucokinase activity and explain part of the increased insulin responsiveness to glucose of the fetal rat β-cell. These observations suggest that GH is of physiological significance for the maturation of the fetal β-cell.

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M J Moreno-Aliaga, M M Swarbrick, S Lorente-Cebrián, K L Stanhope, P J Havel and J A Martínez

We have previously demonstrated that insulin-stimulated glucose metabolism, and not insulin per se, mediates the effects of insulin to increase the transcriptional activity of the leptin promoter in adipocytes. Here, we sought to identify the specific cis-acting DNA elements required for the upregulation of leptin gene transcription in response to insulin-mediated glucose metabolism. To accomplish this, 3T3-L1 cells and primary rat adipocytes were transfected with a series of luciferase reporter genes containing portions of the mouse leptin promoter. Using this method, we identified an element between −135 and −95 bp (relative to the transcriptional start site) that mediated transcription in response to insulin-stimulated glucose metabolism in adipocytes. This effect was abolished by incubation with 2-deoxy-d-glucose, a competitive inhibitor of glucose metabolism. Gel shift electrophoretic mobility shift assays confirmed that the stimulatory effect of insulin-mediated glucose metabolism on leptin transcription was mediated by a previously identified Sp1 site. Consistent with these findings, incubation of primary rat adipocytes with WP631, a specific inhibitor of specificity protein (Sp)1-dependent transcription, inhibited glucose- and insulin-stimulated, but not basal, leptin secretion. Together, these findings support a key role for Sp1 in the transcriptional activation of the leptin gene promoter by insulin-mediated glucose metabolism.

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F Al-Khafaji, M Wiltshire, D Fuhrer, G Mazziotti, M D Lewis, P J Smith and M Ludgate

Epidemiological studies have revealed a significantly higher incidence of toxic adenoma (TA) and toxic multi-nodular goitre (TMNG) in regions of iodine deficiency. Fifty to eighty percent of TA and TMNG are caused by activation of the cAMP pathway, mostly by mutations in the thyrotrophin receptor (TSHR).

We aimed to investigate whether iodide could modulate the biological effects of activating TSHR mutations. We have applied an in vitro model of TA comprising FRTL-5 cells stably expressing activating TSHR. We have mimicked the in vivo situation by examining the effects of prolonged exposure to iodide on the proliferation and signal transduction etc. of these cells.

We observed an iodide-induced ‘inhibition of proliferation’ which was significant from 10 mM in the presence of serum but from 1 mM in its absence. The inhibition of proliferation was significantly higher in the activating mutant expressing FRTL-5 compared with control Neo or wild-type TSHR, indicating that the effect was mediated via the cAMP cascade. The effect was neither due to hyper-tonicity nor was it the result of an increase in cell death either by apoptosis or necrosis. Prolonged exposure to iodide produces an increase in cells in the G2 and post-G2 phases, indicating that G2/M blockade contributes to the mechanism of inhibition.

The mutant expressing FRTL-5 cells have increased proliferation when chronically exposed to TSH, and this is associated with a reduction in phosphorylated (p) CREB levels. This contrasts with the effect of iodide in which inhibition of proliferation is accompanied by an increase in pCREB.

In conclusion, our studies indicate that the biological effects of activating TSHR mutations vary with the ambient iodide supply and could be masked in regions of high iodine intake.

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Suryaprakash Raichur, Song Hooi Teh, Kenji Ohwaki, Vidhi Gaur, Yun Chau Long, Mark Hargreaves, Sean L McGee and Jun Kusunoki

The class IIa histone deacetylases (HDACs) act as transcriptional repressors by altering chromatin structure through histone deacetylation. This family of enzymes regulates muscle development and phenotype, through regulation of muscle-specific genes including myogenin and MyoD (MYOD1). More recently, class IIa HDACs have been implicated in regulation of genes involved in glucose metabolism. However, the effects of HDAC5 on glucose metabolism and insulin action have not been directly assessed. Knockdown of HDAC5 in human primary muscle cells increased glucose uptake and was associated with increased GLUT4 (SLC2A4) expression and promoter activity but was associated with reduced GLUT1 (SLC2A1) expression. There was no change in PGC-1 α (PPARGC1A) expression. The effects of HDAC5 knockdown on glucose metabolism were not due to alterations in the initiation of differentiation, as knockdown of HDAC5 after the onset of differentiation also resulted in increased glucose uptake and insulin-stimulated glycogen synthesis. These data show that inhibition of HDAC5 enhances metabolism and insulin action in muscle cells. As these processes in muscle are dysregulated in metabolic disease, HDAC inhibition could be an effective therapeutic strategy to improve muscle metabolism in these diseases. Therefore, we also examined the effects of the pan HDAC inhibitor, Scriptaid, on muscle cell metabolism. In myotubes, Scriptaid increased histone 3 acetylation, GLUT4 expression, glucose uptake and both oxidative and non-oxidative metabolic flux. Together, these data suggest that HDAC5 regulates muscle glucose metabolism and insulin action and that HDAC inhibitors can be used to modulate these parameters in muscle cells.

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W Becker, R Kluge, T Kantner, K Linnartz, M Korn, G Tschank, L Plum, K Giesen and HG Joost

New Zealand obese (NZO) mice exhibit severe insulin resistance of hepatic glucose metabolism. In order to define its biochemical basis, we studied the differential expression of genes involved in hepatic glucose and lipid metabolism by microarray analysis. NZOxF1 (SJLxNZO) backcross mice were generated in order to obtain populations with heterogeneous metabolism but comparable genetic background. In these backcross mice, groups of controls (normoglycemic/normoinsulinemic), insulin-resistant (normoglycemic/hyperinsulinemic) and diabetic (hyperglycemic/hypoinsulinemic) mice were identified. At 22 weeks, mRNA was isolated from liver, converted to cDNA, and used for screening of two types of cDNA arrays (high-density filter arrays and Affymetrix oligonucleotide microarrays). Differential gene expression was ascertained and assessed by Northern blotting. The data indicate that hyperinsulinemia in the NZO mouse is associated with: (i) increased mRNA levels of enzymes involved in lipid synthesis (fatty acid synthase, malic enzyme, stearoyl-CoA desaturase) or fatty acid oxidation (cytochrome P450 4A14, ketoacyl-CoA thiolase, acyl-CoA oxidase), (ii) induction of the key glycolytic enzyme pyruvate kinase, and (iii) increased mRNA levels of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase. These effects were enhanced by a high-fat diet. In conclusion, the pattern of gene expression in insulin-resistant NZO mice appears to reflect a dissociation of the effects of insulin on genes involved in glucose and lipid metabolism. The data are consistent with a hypothetical scenario in which an insulin-resistant hepatic glucose production produces hyperinsulinemia, and an enhanced insulin- and substrate-driven lipogenesis further aggravates the deleterious insulin resistance of glucose metabolism.

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L. A. Berry and P. Skett

ABSTRACT

The effects of various concentrations of cyclic AMP (cAMP) on the metabolism of androst-4-ene-3,17-dione were examined in electropermeabilized rat hepatocytes. cAMP had a biphasic effect on hepatic steroid metabolism which was dependent upon [ill] concentration and time. At low concentrations (50 μm) early (1 h) inhibitory effects predominated, whereas at higher concentrations (5 mm) later (2–3 h) stimulatory effects were seen. The use of selective protein kinase inhibitors indicated that all the effects of cAMP were mediated through activation of protein kinase A, but that the inhibitory response also involved activation of protein kinase C. The stimulatory effect was blocked by cycloheximide, indicating that protein synthesis is necessary for this response. These findings help to elucidate the mechanisms by which hormones and other compounds may give their effects on hepatic steroid metabolism and indicate a possibly novel interaction of cAMP and protein kinase C.

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C Wrutniak-Cabello, F Casas and G Cabello

Triiodothyronine (T3) is considered a major regulator of mitochondrial activity. In this review, we show evidence of the existence of a direct T3 mitochondrial pathway, and try to clarify the respective importance of the nuclear and mitochondrial pathways for organelle activity. Numerous studies have reported short-term and delayed T3 stimulation of mitochondrial oxygen consumption. Convincing data indicate that an early influence occurs through an extra-nuclear mechanism insensitive to inhibitors of protein synthesis. Although it has been shown that diiodothyronines could actually be T3 mediators of this short-term influence, the detection of specific T3-binding sites, probably corresponding to a 28 kDa c-Erb Aalpha1 protein of the inner membrane, also supports a direct T3 influence. The more delayed influence of thyroid hormone upon mitochondrial respiration probably results from mechanisms elicited at the nuclear level, including changes in phospholipid turnover and stimulation of uncoupling protein expression, leading to an increased inner membrane proton leak. However, the involvement of a direct mitochondrial T3 pathway leading to a rapid stimulation of mitochondrial protein synthesis has to be considered. Both pathways are obviously involved in the T3 stimulation of mitochondrial genome transcription. First, a 43 kDa c-Erb Aalpha1 protein located in the mitochondrial matrix (p43), acting as a potent T3-dependent transcription factor of the mitochondrial genome, induces early stimulation of organelle transcription. In addition, T3 increases mitochondrial TFA expression, a mitochondrial transcription factor encoded by a nuclear gene. Similarly, the stimulation of mitochondriogenesis by thyroid hormone probably involves both pathways. In particular, the c-erb Aalpha gene simultaneously encodes a nuclear and a mitochondrial T3 receptor (p43), thus ensuring coordination of the expression of the mitochondrial genome and of nuclear genes encoding mitochondrial proteins. Recent studies concerning the physiological importance of the direct mitochondrial T3 pathway involving p43 led to the conclusion that it is not only involved in the regulation of fuel metabolism, but also in the regulation of cell differentiation. As the processes leading to or resulting from differentiation are energy-consuming, p43 coordination of metabolism and differentiation could be of significant importance in the regulation of development.

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Gábor Bánhegyi, Miklós Csala and Angelo Benedetti

Hexose-6-phosphate dehydrogenase (H6PD) got into the focus of interest due to its role in the prereceptorial activation of glucocorticoids, which has been implicated in the pathomechanism of metabolic syndrome. Genetic observations, results gained in H6PD knockout mice, and studies on differentiating adipocytes demonstrated the importance of the enzyme in metabolic regulation. A nutrient-sensing function can be postulated for the enzyme, which links metabolism to endocrinology in the endoplasmic reticulum. This review provides an overview of the recent developments concerning the enzyme and its impact on various branches of the intermediary metabolism, which make it an important subject for the research on obesity, diabetes, and metabolic syndrome.