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PubMed1999

Distribution of neurturin mRNA and immunoreactivity in the peripheral tissues of adult rats.

Neurturin (NTN) is a recently discovered neurotrophic factor related to glial cell line-derived neurotrophic factor (GDNF) and has a wide spectrum of biological roles in different types of neurons in the central and peripheral nervous systems. However, information on its expression in peripheral tissues has been limited, and there is no information on its peptide distribution. As a step to examine its role and action mechanisms in neuronal and non-neuronal cells in the periphery, the present study investigated the distribution patterns of its mRNA and peptide in some major peripheral organs of adult rats by in situ hybridization and immunohistochemistry. A widespread expression of NTN mRNA was found in the selected organs of various systems, with a high level in pituitary intermediate lobe, intestine, salivary gland, and testis, and a moderate level in ovary, adrenal gland, kidney, thyroid, and spleen. NTN peptide was also present in the peripheral organs studied, with its distribution corresponding to that of mRNA. In conclusion, NTN is expressed widely in many regionally well-defined cellular systems in various peripheral tissues, suggesting that NTN may act as a target-derived neurotrophic factor for innervating neurons and may have maintenance functions in non-neuronal cells of these adult organs.

Adrenal Glands↗
PubMed1989

Diazepam binding inhibitor-like immunoreactivity(51-70): distribution in human brain, spinal cord and peripheral tissues.

We have used a specific radioimmunoassay to describe the distribution of diazepam binding inhibitor-like immunoreactivity (DBI-IR(51-70) in human post-mortem tissues. In brain, highest concentrations were found in the cerebellum, amygdala, hippocampus, hypothalamus and substantia nigra. In the spinal cord, DBI-IR(51-70) was evenly distributed. In peripheral tissues, highest concentrations were found in the liver and kidney. Chromatographic analysis revealed several molecular forms of DBI-IR(51-70) the major form being of greater molecular weight and hydrophobicity than the synthetic fragment peptide. In peripheral tissues, but not in the CNS, a small peak of immunoreactivity was indistinguishable from the synthetic peptide. DBI-IR(51-70) is therefore widespread, but tissue processing may be different.

Aged↗
PubMed1994

Methionine-enkephalin concentrations in discrete brain regions, spinal cord, pituitary gland and peripheral tissues of U-50,488H-tolerant and abstinent rats.

Effects were determined of chronic administration and withdrawal of a highly selective kappa-opioid receptor agonist, U-50,488H, on methionine-enkephalin levels in central and peripheral tissues of male Sprague-Dawley rats. Rats were rendered tolerant to and physically dependent on U-50,488H by twice daily injections of 25 mg/kg of this compound for 5 days. Rats deemed abstinent were injected with this drug for 4 days and sacrificed on 5th day. Methionine-enkephalin concentration increased in the hippocampus of U-50,488H-tolerant-dependent rats, whereas in abstinent rats, its level was elevated only in the hypothalamus. Levels of methionine-enkephalin in the pituitary gland of U-50,488H-tolerant-dependent or abstinent rats were unchanged. Among peripheral tissues, methionine-enkephalin concentration decreased in the adrenal gland of U-50,488H-tolerant-dependent rats. In the U-50,488H-abstinent rats, methionine-enkephalin concentration was elevated in the heart. In tissues of morphine- and U-50,488H-tolerant-dependent and abstinent rats methionine-enkephalin concentrations were affected differentially, suggesting inherent differences in mu- and kappa-opiate-mediated tolerance-dependence and abstinence processes.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed2006

Circadian clocks are resounding in peripheral tissues.

Circadian rhythms are prevalent in most organisms. Even the smallest disturbances in the orchestration of circadian gene expression patterns among different tissues can result in functional asynchrony, at the organism level, and may to contribute to a wide range of physiologic disorders. It has been reported that as many as 5%-10% of transcribed genes in peripheral tissues follow a circadian expression pattern. We have conducted a comprehensive study of circadian gene expression on a large dataset representing three different peripheral tissues. The data have been produced in a large-scale microarray experiment covering replicate daily cycles in murine white and brown adipose tissues as well as in liver. We have applied three alternative algorithmic approaches to identify circadian oscillation in time series expression profiles. Analyses of our own data indicate that the expression of at least 7% to 21% of active genes in mouse liver, and in white and brown adipose tissues follow a daily oscillatory pattern. Indeed, analysis of data from other laboratories suggests that the percentage of genes with an oscillatory pattern may approach 50% in the liver. For the rest of the genes, oscillation appears to be obscured by stochastic noise. Our phase classification and computer simulation studies based on multiple datasets indicate no detectable boundary between oscillating and non-oscillating fractions of genes. We conclude that greater attention should be given to the potential influence of circadian mechanisms on any biological pathway related to metabolism and obesity.

Adipose Tissue↗
PubMed1989

Arachidonic acid as a possible modulator of estrogen, progestin, androgen, and glucocorticoid receptors in the central and peripheral tissues.

In an attempt to learn whether modulation of steroid hormone receptor by arachidonate is generalized or not, the arachidonate effect was examined in cytosol estrogen (ER), progestin (PR), androgen (AR) and glucocorticoid receptors (GCR) from the central and peripheral tissues of rats by sucrose density gradient centrifugation, and gel filtration on LH20 columns or dextran-coated charcoal absorption. Arachidonate and other long-chain fatty acids appear to inhibit the specific binding of estrogen ([3H]R2858), progestin ([3H]R5020), androgen ([3H]R1881) and glucocorticoid ([3H]dexamethasone) to the respective receptors in brain (neonatal cerebral cortex and hypothalamus-preoptic area, HPOA), uterus and prostate, with the exception of the potentiating effect on the brain estrogen receptors. The potency of the unsaturated fatty acids paralleled to some degree the number of cis double bonds and carbon, in that oleate (C18:1) arachidonate (C20:4) docosahexaenoate (C22:6). The arachidonate inhibition was dose-dependent in the tissue steroid hormone receptors, except for dose-dependent potentiation of the brain cortical estrogen receptors. Inhibitory potency as expressed by the concentration for 50% maximum inhibition (Ki) was in the range of 11-18 microM for the receptors other than the uterine estrogen receptors with the value of 44 microM, suggesting lower sensitivity for the estrogen receptor to the arachidonate effect in the uterus. Analysis on kinetics and Scatchard plot revealed the non-competitive type of the inhibition. In addition, arachidonate lowered dose-dependently the peak of labelled progestin or estrogen binding to the 8S receptor proteins, which were collected from fractions in the 8S region of the cytosols from intact or diethylstibestrol-primed rat uteri. These results suggest the generalized modulatory effect of arachidonate on the steroid hormone receptors in the central and peripheral tissues. Arachidonate could affect, negatively or positively, the estrogen receptors, and negatively the progestin, androgen and glucocorticoid receptors, through a possibly direct but weak binding at sites different from steroid binding sites on the receptor molecules. A potential messenger role of arachidonate itself has been implicated in the regulation or modulation of the steroid hormone receptors.

Animals↗
PubMed1995

["Intracrinology". Autonomy and freedom of peripheral tissues].

Hormone-sensitive cancers, namely those of the prostate, breast and uterus, constitute one third of all cancers. In addition to the classical steroidogenic tissues, namely the ovaries, testes, adrenals and placenta, a large series of peripheral tissues possess all the enzymatic systems required for the formation of active androgens and estrogens from a relatively large supply of precursor steroids namely, dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) provided by the adrenals. This report describes the structure, function and tissue-specific expression and regulation of the 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4 isomerase, 17 beta-hydroxysteroid dehydrogenase, 5 alpha-reductase gene families as well as some information about the aromatase gene. While, so far, most therapeutical approaches have been aimed and limited at controlling steroid formation by the classical steroidogenic tissues, it is clear that major efforts should now be turned towards intracrinology in order to better understand the physiological mechanisms controlling local steroid formation in peripheral target tissues and to develop improved therapy for hormono-sensitive diseases, especially breast, prostate, and uterine cancers.

17-Hydroxysteroid Dehydrogenases↗
PubMed1996

Isolation and measurement of the endogenous cannabinoid receptor agonist, anandamide, in brain and peripheral tissues of human and rat.

Anandamide (arachidonylethanolamide) is a novel lipid neurotransmitter first isolated from porcine brain which has been shown to be a functional agonist for the cannabinoid CB1 and CB2 receptors. Anandamide has never been isolated from human brain or peripheral tissues and its role in human physiology has not been examined. Anandamide was measured by LC/MS/MS and was found in human and rat hippocampus (and human parahippocampal cortex), striatum, and cerebellum, brain areas known to express high levels of CB1 cannabinoid receptors. Significant levels of anandamide were also found in the thalamus which expresses low levels of CB1 receptors. Anandamide was also found in human and rat spleen which expresses high levels of the CB2 cannabinoid receptor. Small amounts of anandamide were also detected in human heart and rat skin. Only trace quantities were detected in pooled human serum, plasma, and CSF. The distribution of anandamide in human brain and spleen supports its potential role as an endogenous agonist in central and peripheral tissues. The low levels found in serum, plasma, and CSF suggest that it is metabolized in tissues where it is synthesized, and that its action is probably not hormonal in nature.

Animals↗
PubMed1984

Vitamin E concentrations in the brains and some selected peripheral tissues of selenium-deficient and vitamin E-deficient mice.

Weanling male CD-l mice were fed control, vitamin E-deficient or selenium-deficient diets for periods of 12 to 20 weeks. alpha-Tocopherol concentrations in plasma, liver, and testes, as well as in three specific areas in the brain (cerebral hemisphere, cerebellum, and medulla plus pons) were determined by high performance liquid chromatography. Significant concentrations of alpha-tocopherol were found in all brain samples from vitamin E-deficient animals long after the peripheral tissues were depleted, indicating that brain is more resistant to vitamin E deficiency than peripheral tissues. Cerebellar concentrations of alpha-tocopherol were consistently lower than those of cerebral hemisphere and medulla-pons. Furthermore, the cerebellar alpha-tocopherol concentration sustained a larger decline than the other two brain areas within 6 weeks of vitamin E deficiency treatment. These and other data suggest that cerebellum may be more susceptible to damage from vitamin E deficiency than other parts of the brain. Selenium deficiency did not affect brain alpha-tocopherol concentrations during the 12 weeks of the study.

Animals↗
PubMed1987

Localization of mRNAs encoding the alpha-subunits of signal-transducing G-proteins within rat brain and among peripheral tissues.

The sequence of the mRNAs which encode the alpha-subunits of the signal-transducing G-proteins Gs, Go and two forms of Gi (termed Gi1 and Gi2) have recently been reported. Based on rat sequences we prepared oligodeoxynucleotide probes for measurement of these mRNAs in rat brain and peripheral tissues. The relative abundance of these mRNA species in brain was Gs greater than Go approximately Gi2 greater than Gi1. The Gs and Gi2 mRNAs had somewhat lower levels in heart, kidney and liver than in brain, and Go and Gi1 mRNAs were not detected in the peripheral tissues. Using in situ hybridization we localized each of these mRNAs within slices of the rat brain. The patterns of distribution of Gs and Gi2 mRNA were very similar, but very different from that of Go and Gi1 mRNA. These data illustrate that receptor-effector coupling G-proteins are regionally specialized in their expression. This regional specialization may reflect a selective coupling of individual G-proteins with the various neurotransmitter receptors and effector pathways.

Animals↗
PubMedDate not supplied

Phenylalanine utilization in brain and peripheral tissues during development in normal and protein malnourished rats.

Rats born of mothers fed a low protein diet (8% casein) compared to control rats on a normal diet (25% casein) started 5 weeks prior to mating showed significant increases in uptake, incorporation and percent incorporation into protein of 14C-phynylalanine into brain and peripheral tissues. These effects were most pronounced on the day of birth. Also, different patterns of uptake of radioactive phenylalanine were observed between the two diet groups at birth. At ages 5, 11 and 21 days the 8% casein rats showed significant increases only in uptake and incorporation of 14C-phenylalanine into brain tissues as compared to the 25% casein animals with the percent incorporation of total radioactivity into brain protein being the same for both diet groups. For the most part, there were no significant changes in uptake and incorporation of radioactivity in peripheral tissues for the two diet groups on these post-birth days. Overall, the data indicate the possible presence of a brain specific effect whereby preferential utilization of an essential amino acid (phenylalanine) by the central nervous system occurs when rats are fed a low protein diet.

Age Factors↗
PubMed1984

Differential roles of splanchnic and peripheral tissues in the pathogenesis of impaired glucose tolerance.

To identify the mechanism(s) of the altered glucoregulatory response to a glucose load in subjects with impaired glucose tolerance, we selectively quantitated the components of net splanchnic glucose balance, i.e., splanchnic glucose uptake and hepatic glucose output, as well as peripheral glucose uptake, by combining [3-3H]glucose infusion with hepatic vein catheterization. After intravenous glucose infusion (6 mg X kg-1 X min-1 for 90 min), blood glucose rose to 172 +/- 7 mg/dl in controls and 232 +/- 13 mg/dl in subjects with impaired glucose tolerance (P less than 0.01). The response of plasma insulin did not differ significantly between the two groups (29 +/- 4 vs. 40 +/- 10 microU/ml at 90 min in control and in glucose intolerant subjects, respectively; P = NS). In both groups, glucose infusion caused the net splanchnic glucose balance to switch from the net output of the basal state to a net glucose uptake. However, this effect was more marked in subjects with impaired glucose tolerance than in control subjects (at 90 min: 2.83 +/- 0.53 vs. 1.60 +/- 0.18 mg X kg-1 X min-1, respectively: P less than 0.05). The different pattern of splanchnic glucose balance was entirely accounted for by a greater rise in splanchnic glucose uptake in the group of glucose intolerants , as the suppression of endogenous glucose output by the glucose load was practically complete in both groups. In contrast, glucose uptake by peripheral tissues increased considerably less in subjects with impaired glucose tolerance than in controls (2.2-2.6 vs 3.6-4.1 mg X kg-1 X min-1, respectively, between 60 and 90 min; P less than 0.01-0.001). Furthermore, a net splanchnic lactate uptake was present in the basal state, which was inhibited by the glucose load and switched to a comparable net lactate output in both groups. These results indicate that the mechanism responsible for the altered glucoregulation in subjects with impaired glucose tolerance resides entirely in the peripheral tissues whose ability to dispose of a glucose load is drastically reduced. On the other hand, no defect is detectable in any of the explored mechanisms regulating splanchnic glucose metabolism during the disposal of an exogenous glucose load.

Blood Glucose↗
PubMed1999

Pre- and postprandial expression of the leptin receptor splice variants OB-Ra and OB-Rb in murine peripheral tissues.

Leptin receptors (OB-R) are widely distributed in peripheral tissues. However, the RT-PCR data published on the distribution of OB-R are not always consistent. The present study was undertaken in order to test whether the different muscle fiber type profile or the acute nutritional status in which tissue samples were excised from animals may influence OB-R expression. Six 12-week-old male Swiss-Webster mice were killed by decapitation either 1 h after feeding or after a 16-h fast, and the kidneys, testes, brown adipose tissue, gastrocnemius (G), soleus (SOL) and extensor digitorum longus (EDL) muscles were dissected out. In parallel, muscle fibers obtained from other animals were classified on the basis of differences in the staining intensity for myofibrillar adenosinetriphosphatase. The expression of OB-R isoforms was assessed by RT-PCR and ethidium bromide staining. The signal for OB-Ra and OB-Rb was detected in all tissues examined. No differences were observed in samples obtained from either fed or fasted mice. G, SOL and EDL muscles showed the same pattern of OB-R expression. Neither the short-term nutritional changes of the animal as regards to the pre- versus the postprandial-state nor differences in muscle fiber type had any influence on the qualitative expression of the OB-R splice variants a and b in the murine tissues studied. However, quantitative differences cannot be ruled out.

Animals↗
PubMed1976

Lack of in vivo transformation of human growth hormone to its "activated" isohormones in peripheral tissues of the rhesus monkey.

Human growth hormone (hGH) B can be transformed to its biologically more active isohormones C, D and E by limited proteolysis with plasmin in vitro, but the physiological significance of this observation is not known. The possible occurrence of such an "activation process" in peripheral tissues was investigated in the rhesus monkey. Radioiodinated hGH (B, C) or isolated hGH-B were injected intravenously into 4 rhesus monkeys and blood samples were drawn at frequent intervals. Analysis of circulating hGH was carried out by precipitation of hGH with trichloroacetic acid (TCA) and excess anti-hGH antibody, and by polyacrylamide gel electrophoresis followed by autoradiography. The metabolic clearance rate, based on TCA-precipitable radioactivity, was 2.36 +/- 1.17 ml/min/kg (mean +/- SD), similar to that reported for man. No evidence for the presence of circulating hGH-D or E was found, although progressive accumulation of smaller radioactive fragments and free iodide was observed. It is concluded that peripheral tissues or plasma enzymes probably do not convert significant amounts of hGH-B or C to their more active charge isomers, at least in the monkey. Therefore, if enzymatic activation of hGH does occur in vivo, the pituitary gland would seem the most likely site for such a process.

Animals↗
PubMed2000

[Peripheral tissue microdialysis technique in unrestrained, conscious animals].

The microdialysis procedure had been developed in the past 2 to 3 decades to determine levels of drug and endogenous compounds in several organs under physiological conditions. Advantages of microdialysis include: minimal stress on the experimental animals; studies may be done in unrestrained, conscious animals, and multiple determination can be made without concern for excess blood loss from small animals; and measurements can be made of drug and/or metabolites at multiple sites in the animal. By employing the microdialysis technique, I developed the method of multiple sampling for a long term period from an animal under the freely moving condition. In addition, I developed a novel microdialysis probe that was applied to several peripheral tissues and/or organs. In this paper, I will describe the fundamental procedure for peripheral tissues and/or organs such as the jugular vein and liver, using subcutaneous and ocular microdialysis sampling in unrestrained, conscious animals.

Animals↗
PubMed1987

Obese (ob/ob) and diabetes (db/db) mutations: two factors modulating brain and peripheral tissue accumulation of estradiol in C57BL/KsJ mice.

The effect of two mutant genes for obesity (ob/ob) and diabetes (db/db) on the accumulation rate of radiolabeled estradiol was examined in female C57BL/KsJ mice. Mutant mice were match-paired with normal (+/?) animals at 16 weeks of age. All ob/ob and db/db mice exhibited overt obesity and hyperglycemia relative to normals. The distribution and uptake of the radiolabeled estradiol was subsequently examined in specified CNS and peripheral tissues. In all cases, the db/db and ob/ob mutant conditions resulted in a depressed cellular accumulation of radiolabeled estradiol in both CNS and peripheral tissues relative to normal mice. The ob/ob mutation resulted in a more severe depression of tissue estradiol uptake than did the db/db mutation. These studies indicate that the abnormal metabolic and hormonal states induced by the mutations, and not the mere presence of the genomic mutation itself, probably accounts for the depressed cellular affinity for gonadal steroids in these murine models.

Animals↗
PubMed2000

The expression of GABA(B1) and GABA(B2) receptor subunits in the cNS differs from that in peripheral tissues.

GABA(B) receptors are G-protein-coupled receptors that mediate the slow and prolonged synaptic actions of GABA in the CNS via the modulation of ion channels. Unusually, GABA(B) receptors form functional heterodimers composed of GABA(B1) and GABA(B2) subunits. The GABA(B1) subunit is essential for ligand binding, whereas the GABA(B2) subunit is essential for functional expression of the receptor dimer at the cell surface. We have used real-time reverse transcriptase-polymerase chain reaction to analyse expression levels of these subunits, and their associated splice variants, in the CNS and peripheral tissues of human and rat. GABA(B1) subunit splice variants were expressed throughout the CNS and peripheral tissues, whereas surprisingly GABA(B2) subunit splice variants were neural specific. Using novel antisera specific to individual GABA(B) receptor subunits, we have confirmed these findings at the protein level. Analysis by immunoblotting demonstrated the presence of the GABA(B1) subunit, but not the GABA(B2) subunit, in uterus and spleen. Furthermore, we have shown the first immunocytochemical analysis of the GABA(B2) subunit in the brain and spinal cord using a GABA(B2)-specific antibody. We have, therefore, identified areas of non-overlap between GABA(B1) and GABA(B2) subunit expression in tissues known to contain functional GABA(B) receptors. Such areas are of interest as they may well contain novel GABA(B) receptor subunit isoforms, expression of which would enable the GABA(B1) subunit to reach the cell surface and form functional GABA(B) receptors.

Animals↗
PubMed1994

Distribution of TRH-potentiating peptide (Ps4) and its receptors in rat brain and peripheral tissues.

TRH-potentiating peptide (Ps4) is a peptide originally isolated from bovine hypothalamus, which corresponds to the deduced rat prepro-TRH-(160-169) sequence. We have examined the distribution of Ps4 and [125I-Tyr0]Ps4 binding sites in various rat tissues. Very high specific binding of [125I-Tyr0]Ps4 was observed in pituitary membranes. Almost identical relative magnitude of binding was found in spinal cord, hypothalamus, hippocampus and olfactory lobe. In addition, a high density of Ps4 binding sites was demonstrated in urogenital organs. The observed distribution pattern of Ps4 in brain tissues was similar to that reported for TRH, with high concentrations in the hypothalamus and significant amount in spinal cord and olfactory lobe. These findings support the hypothesis that the TRH-potentiating peptide could act as neuromodulator or neurotransmitter in the central nervous system (CNS). In peripheral tissues, very low concentrations of Ps4 were detected except in testis which seems to be the major locus for Ps4 biosynthesis. This study demonstrated for the first time that TRH-potentiating peptide and its receptors are widely distributed in the CNS and peripheral tissues.

Animals↗
PubMed1991

Neutral endopeptidase 24.11 in rat peripheral tissues: comparative localization by 'ex vivo' and 'in vitro' autoradiography.

The neutral endopeptidase 24.11 (NEP) also called 'enkephalinase' thanks to its inactivation of enkephalins in the brain, was also recently shown to be involved in the degradation of the circulating atrial natriuretic peptide (ANP). Inhibitors of NEP are therefore under clinical trials as new analgesics or antidiarrheal agents, protecting centrally or peripherally released opioid peptides and as novel antidiuretics and anti-hypertensives in prolonging the renal and vascular actions of NEP. It was therefore important from a clinical point of view to investigate the distribution in peripheral tissue of a systemically administered NEP blocker. Different concentrations of the radiolabelled inhibitor [3H]HACBO-Gly have been intravenously injected in rat and the distribution studied using whole-body sections at different times by 'ex vivo' and 'in vitro' autoradiography to investigate differences in tissue accessibility of NEP to a circulating inhibitor. In vivo [3H]HACBO-Gly binding was fully prevented by an excess of unlabelled inhibitor and disappeared rapidly mainly through renal elimination. NEP labelling was prominent in kidney, liver, lung, fat deposits in the neck region, the flat bones of the skull, the mandibula, the vertebrae, the long bones of the limbs, articular cartilages and synoviae. A lower labelling was found in the intestine, the glomeruli and the submaxillary glands. [3H]HACBO-Gly binds also to a limited number of peripheral tissues in which the presence of NEP was yet unknown (bones, parts of adipose tissues. Some tissues, not labelled in vivo, exhibited various degrees of labelling under in vitro conditions (the brain, some portions of the gut, the testes, the prostate). Interestingly, few lobules of the submaxillary glands were much more densely labelled suggesting the possible occurrence of NEP heterogeneity. Except for the brain, the physiological function of NEP in various tissues remains largely unknown, but this ectoenzyme is likely involved in inactivation of regulatory peptides such as: ANP (partially in the kidney), SP in the lung and possibly somatostatin and ANP in bone, ANP in adipose tissue, enkephalin in testes, immune peptidic factors in bone marrow. A part of NEP in bone marrow corresponds probably to the common acute lymphoblastic antigen, CALLA, densely expressed on pre-B cells. Finally, it is important to notice that several tissues containing important concentrations of NEP (brain, testes, prostate, eye, gut, brush border) are inaccessible to the i.v. injected inhibitor thanks to the presence of functional barriers.

Animals↗