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PubMed1993

Different (13)CO(2) recovery of orally administered [1-(13)C]- and [8-(13)C] triolein in postprandial humans: an effect of phosphoenolpyruvate-carboxykinase (EC 4.1.1.32) in peripheral tissues?

In this study the conversion of orally administered [1-(13)C]- and [8-(13)C]triolein to CO(2) was compared in normal postprandial human subjects (3 female, 3 male). After an overnight fast the subjects consumed hourly meals of a liquid formula diet over 12 h (8.3% of the predicted 24 h resting energy expenditure/h). 90 min after the first meal on one occasion a bolus of [1-(13)C]triolein was given and in the repeat study the same subject received [8-(13)C]triolein. The order of isotope substrate was randomized. Isotope ratio mass spectrometry analysis of breath samples an recorded CO(2) production rate resulted in a significant 1.31 times greater (13)CO(2) recovery of [1-(13)C]triolein compared to [8-(13)C]triolein within 7.5 h. 10 h after bolus the significant difference disappeared. The different (13)CO(2) recovery is probably due to a different metabolic fate of (13)C at odd and even numbered carbon positions in the fatty acid chain caused by beta-oxidation, citric acid cycle and the phosphoenolpyruvate carboxykinase (EC 4.1.1.32) reaction in peripheral tissues. A contribution of a chain shortening in peroxisomes seems unlikely.

Journal Article↗
PubMed1997

The developmental expression in the rat CNS and peripheral tissues of proteases PC5 and PACE4 mRNAs: comparison with other proprotein processing enzymes.

Many peptides modulating cellular growth and differentiation in development are first synthesized as precursors that require proteolytic processing by the "prohormone convertase" (PC) family of endoproteases. Using in situ hybridization, we have here determined that two recently identified PC members, PC5 and PACE4, are expressed prenatally in spatial and temporal patterns that are each unique and distinct from those of previously characterized PCs. PC5 mRNA is first detected at e9 in highly restricted regions of the neural tube, in caudal myotomes, and at the materno-embryonic junction of the uterus. At e10, restricted PC5 mRNA expression is detected in the optic and otic vesicles, the roof of midbrain, and trunk myotomes. By midgestation (e13-e16), PC5 mRNA expression in the developing nervous system has expanded to multiple regions including hippocampus, thalamus, hypothalamus, brain stem, and spinal cord. By midgestational stages, PACE4 mRNA is expressed in multiple regions of the developing nervous system, generally distinct from PC5, and including a uniquely high level of expression in the ventricular zone of the hippocampus. In several peripheral organ systems, including lung and gut, we observed remarkably complementary patterns of PC5 and PACE4 expression. In addition, PACE4 transcripts are expressed in the heart and liver, whereas PC5 is expressed in the adrenal and kidney primordia. These results suggest that both PC5 and PACE4 may be involved in neuropeptide precursor processing in the developing nervous system and peripheral tissues with the general nonoverlapping expression patterns suggesting that PC5 and PACE4 may process distinct sets of proprotein substrates.

Animals↗
PubMed2005

Rapid modulation of TRH and TRH-like peptide levels in rat brain and peripheral tissues by corticosterone.

Disturbance of glucocorticoid signaling has been implicated in several neuropsychiatric disorders including unipolar and bipolar depression and anxiety induced by maternal deprivation. Antidepressants have been shown to be neuroprotective and able to reverse damage to glia and neurons. Thyrotropin-releasing hormone (TRH) is an endogenous antidepressant that reduces the expression of glycogen synthase kinase-3beta (GSK-3beta), an enzyme that hyperphosphorylates tau and is implicated in bipolar depression, diabetes and Alzheimer's disease. In order to understand the potential role of TRH and TRH-like peptides both as mediators of the depressogenic effects of glucocorticoids and as potential therapeutics for neuropsychiatric disease, 300 g male Sprague-Dawley rats were injected i.p. with 4 mg corticosterone/0.5 ml 50% DMSO+50% ethanol and sacrificed 0, 2, 4 and 8h later. Levels of TRH and TRH-like peptides were measured in various brain regions involved in mood regulation and pancreas and reproductive tissues that mediate the metabolic and reproductive impairments associated with high glucocorticoid levels. Significant increases, ranging from 2- to 12-fold, in TRH or TRH-like peptide levels were observed in almost all brain regions studied at 4h after corticosterone injection. In cerebellum, TRH and TRH-like peptides increased 4-14-fold by 8h. TRH-like peptide levels fell 86-98% at 4h after treatment in testis. TRH, derived only from Leydig cells, was not affected. TRH and TRH-like peptides increased 2-4-fold at 8h in pancreas. TRH and TRH-like peptide concentrations in prostate were not affected by corticosterone up to 8h after injection. The 4h needed to detect a highly significant change in the TRH and TRH-like peptide levels in brain and peripheral tissues is consistent with the mediation of most corticosterone-effects via alterations in gene transcription.

Animals↗
PubMed2001

Human cationic amino acid transporter hCAT-3 is preferentially expressed in peripheral tissues.

At least five distinct carrier proteins form the family of mammalian cationic amino acid transporters (CATs). We have cloned a cDNA containing the complete coding region of human CAT-3. hCAT-3 is glycosylated and localized to the plasma membrane. Transport studies in Xenopus laevis oocytes revealed that hCAT-3 is selective for cationic L-amino acids and exhibits a maximal transport activity similar to other CAT proteins. The apparent substrate affinity and sensitivity to trans-stimulation of hCAT-3 resembles most closely hCAT-2B. This is in contrast to rat and murine CAT-3 proteins that have been reported to display a very low activity and to be inhibited by neutral and anionic L-amino acids as well as D-arginine (Hosokawa, H., et al. (1997) J. Biol. Chem. 272, 8717-8722; Ito, K., and Groudine, M. (1997) J. Biol. Chem. 272, 26780-26786). Also, in adult rat and mouse, CAT-3 has been found exclusively in central neurons. Human CAT-3 expression is not restricted to the brain, in fact, by far the highest expression was found in thymus. Also in other peripheral tissues, hCAT-3 expression was equal to or higher than in most brain regions, suggesting that hCAT-3 is not a neuron-specific transporter.

Amino Acid Sequence↗
PubMed1990

Glyburide increases insulin sensitivity and responsiveness in peripheral tissues of the rat as determined by the glucose clamp technique.

The effect of chronic glyburide treatment on insulin sensitivity and responsiveness in vivo in unanesthetized male Sprague-Dawley rats was determined by the hyperinsulinemic-euglycemic clamp technique. Normal animals were surgically prepared for the clamp procedure and then gavaged with glyburide, 2 mg/kg/day, or with normal saline for 6-18 days. Basal plasma glucose concentrations were significantly lower in glyburide-treated animals compared to controls, but basal plasma insulin concentrations were the same. Rates of glucose disposal, calculated before and during insulin infusions of 2 to 40 mU/kg.min with plasma glucose concentration clamped at 125 mg/dl, were significantly greater in the glyburide-treated rats compared to controls. Insulin dose-response curves demonstrate that glyburide treatment increased both insulin sensitivity and responsiveness. Basal hepatic glucose production, estimated by D-[3-3H]Glucose infusion, was significantly greater with glyburide treatment; however the sensitivity of the liver to suppression by insulin infusions of 2 and 4 mU/kg.min was unchanged. These data suggest that the decreased basal plasma glucose concentration observed in rats chronically treated with glyburide is the result of increased glucose disposal in peripheral tissues and not associated with an increase in plasma insulin concentrations or a decrease in hepatic glucose production.

Animals↗
PubMed2006

STAT1 in peripheral tissue differentially regulates homing of antigen-specific Th1 and Th2 cells.

Th1 and Th2 effector CD4+ T cells orchestrate distinct counterregulatory biological responses. To deliver effective tissue Th1- and Th2-type responses, Th1 and Th2 cell recruitment into tissue must be differentially regulated. We show that tissue-derived STAT1 controls the trafficking of adoptively transferred, Ag-specific, wild-type Th1 cells into the lung. Trafficking of Th1 and Th2 cells is differentially regulated as STAT6, which regulates Th2 cell trafficking, had no effect on the trafficking of Th1 cells and STAT1 deficiency did not alter Th2 cell trafficking. We demonstrate that STAT1 control of Th1 cell trafficking is not mediated through T-bet. STAT1 controls the recruitment of Th1 cells through the induction of CXCL9, CXCL10, CXCL11, and CXCL16, whose expression levels in the lung were markedly decreased in STAT1-/- mice. CXCL10 replacement partially restored Th1 cell trafficking in STAT1-deficient mice in vivo, and deficiency in CXCR3, the receptor for CXCL9, CXCL10, and CXCL11, impaired the trafficking of adoptively transferred Th1 cells in wild-type mice. Our work identifies that STAT1 in peripheral tissue regulates the homing of Ag-specific Th1 cells through the induction of a distinct subset of chemokines and establishes that Th1 and Th2 cell trafficking is differentially controlled in vivo by STAT1 and STAT6, respectively.

Adoptive Transfer↗
PubMed1993

Differential inhibition of 11 beta-hydroxysteroid dehydrogenase by carbenoxolone in rat brain regions and peripheral tissues.

Carbenoxolone (CX), the succinyl ester of glycyrrhetinic acid, causes hypokalemia and hypernatremia. Its pharmacological effects are believed to be due to its inhibition of 11 beta-hydroxysteroid dehydrogenase (11-HSD). There was a marked inhibition of this enzyme in the liver, kidney, pituitary, hippocampus, hypothalamus and amygdala 1 h after intraperitoneal administration of CX (100 mg kg-1) to intact male rats. Intracerebral injection of CX (1.5 mg kg-1) into the 3rd ventricle inhibited the oxidation of corticosterone to 11-dehydrocorticosterone by 11-HSD in the pituitary and hippocampus and produced marked behavioral hyperactivity but had no effect in the liver or kidney. Lower amounts of CX (10-50 micrograms/rat) given intracerebroventricularly (i.c.v) were without significant effect on 11-HSD in the pituitary or amygdala 1 h after infusion but inhibited this enzyme differentially in the hippocampus and hypothalamus. Inhibition of 11-HSD activity in the hippocampus and hypothalamus was observed up to 6 h after i.c.v. administration of CX (50 micrograms/rat) together with some decrease in activity of this enzyme in the pituitary at 3 h. The findings that low doses of CX given i.c.v. can alter the activity of 11-HSD in specific brain regions without affecting its activity in peripheral tissues, and only marginally in the pituitary, provides a method to study the central role of this enzyme independently of systemic effects.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed1988

Enhanced in vitro reactivation of latent herpes simplex virus from neural and peripheral tissues with hexamethylenebisacetamide.

We evaluated the effect of the demethylating agent hexamethylenebisacetamide on reactivation of latent herpes simplex virus type 2 (HSV-2) from guinea pig neural and extraneural tissues. Four explant cultures from the dorsal root ganglia of 42 latently infected guinea pigs and vaginal and cervical explant cultures from 33 animals were divided so that half received 5 mM of hexamethylenebisacetamide supplemented media and half media alone. HSV-2 was recovered earlier and from a greater percentage of treated cultures than controls. For example, seven days after explant, HSV-2 was recovered from 35 of 84 (42%) treated dorsal root ganglia cultures compared to seven of 84 control cultures (p less than 0.0001). Likewise, HSV-2 was recovered seven days after explant from 11 of 66 (17%) treated external genital skin cultures and 2 of 66 control cultures (p less than 0.009), Hexamethylenebisacetamide had no effect on productive HSV-2 infection in guinea pig dorsal root ganglia cultures. This study provides evidence for a role of demethylation in the reactivation of latent HSV from neural as well as peripheral tissues and suggests that latent virus exists at these sites in a similar state. Hexamethylenebisacetamide should be useful in studies of herpes virus latency because it decreases the time necessary to recover virus from latently infected tissues and enhances the recovery of virus.

Acetamides↗
PubMed1979

Insulin resistance in peripheral tissues after a burn injury.

The glucose uptake of a perfused, skin-covered preparation of muscle taken from the rat was altered by prior burn injury to the animal. Animals receiving an 8% deep burn to the back 24 hours prior to testing had a glucose uptake (5.9 +/- 0.85 microM/100 gm/min) which was depressed compared with control nonburned preparations (8.4 +/- 0.34 microM/100 gm/min) (P less than 0.025) at low insulin concentration (35 microU/ml). Higher insulin concentrations (160 microU/ml and 16 microU/ml) produced significant increases in the glucose uptake of both the burned and control animals. At the highest insulin level (16 microU/ml), there was no significant difference between burned and control animals. Preparations from animals burned five days prior to study showed a glucose uptake which was not decreased as compared with control animals at the low level of insulin (35 microU/ml) (7.4 +/- 0.62 microM/100 gm/min), but higher levels of insulin (160 microU/ml and 16 microU/ml) failed to produce a significant increase in glucose uptake (8.4 +/- 0.64 microM/100 gm/min and 8.6 +/- 0.92 microM/100 gm/min, respectively). The values differed significantly (P less than 0.05) from control preparation (11.5 +/- 0.54 microM/100 gm/min) at the insulin level of 16 microU/ml. Two different patterns of altered sensitivity to increased insulin concentrations were noted, depending on the stage of injury. The altered metabolic status of peripheral tissues does contribute to the insulin resistance pheonomenon observed after a burn injury.

Animals↗
PubMed1984

Peripheral tissue mechanism for maintenance of serum triiodothyronine values in a thyroxine-deficient state in man.

The present study was undertaken to define the source of endogenous triiodothyronine (T3) production responsible for maintaining serum T3 levels in euthyroid subjects with depressed serum thyroxine (T4) values. After withdrawal from 4 wk of exogenous T3 administration, a 22% decline in serum T3 values (from 129 +/- 6 to 99 +/- 4 ng/dl) was observed in six euthyroid subjects, despite a twofold reduction in serum T4 concentrations (from 7.5 +/- 0.5 to 3.2 +/- 0.5 micrograms/dl). This was accompanied by a nearly twofold increase in serum T3/T4 ratio values (17 +/- 1 to 29 +/- 6) but no significant alteration in reverse T3/T4 ratio values. This phenomenon did not appear to be thyroid stimulating hormone (TSH) dependent, since base-line serum TSH values were subnormal. Nor was it dependent on changes in thyroid gland function, since a blunted T3 response to exogenous bovine TSH occurred and pharmacologic doses of iodide did not influence the phenomenon. The finding in three athyreotic subjects that serum T3/T4 ratio values increased from 14 +/- 1 on T4 therapy (mean serum T4, 9.6 +/- 0.8 micrograms/dl and T3, 132 +/- 8 ng/dl) to 40 +/- 2 after withdrawal from 2 wk of T3 administration (serum T4 1.2 +/- 0.1 micrograms/dl and T3 46 +/- 3 ng/dl) provided direct evidence that an alteration in peripheral thyroid hormone metabolism was probably responsible for these findings previously observed in euthyroid subjects. The results of this study support the possible existence in euthyroid man of a peripheral tissue autoregulatory mechanism for maintaining serum T3 values in states of T4 deficiency. Whether this process involves an alteration in the efficiency of T4 to T3 conversion or the rate of T3 clearance is presently unknown.

Adult↗
PubMed1990

Androgen binding in peripheral tissues of fetal rhesus macaques: effects of androgen metabolism in liver.

In rhesus monkeys sexual differentiation of the brain and reproductive tract (RT) is androgen-dependent. Presumably these effects are mediated through the androgen receptor (AR). The AR has not been characterized in fetal tissues such as liver, kidney, heart, spinal cord and RT in this species. We characterized AR binding using [3H]R1881 as the ligand in cytosols from tissues obtained on days 100-138 of gestation. Scatchard analyses revealed a single, saturable, high affinity AR in liver, kidney, heart, spinal cord and RT. The apparent dissociation constant (Kd) ranged from 0.52 to 0.85 nM with no significant tissue differences. The number of AR (Bmax; fmol/mg protein) differed significantly (P less than 0.01) between tissues (liver greater than RT much greater than kidney greater than or equal to heart greater than or equal to spinal cord). Radioinert testosterone (T) and 5 alpha-dihydrotestosterone (DHT) but not androstenedione, progesterone, estradiol-17 beta, estrone or cortisol in a 50-fold molar excess inhibited [3H]R1881 binding to the AR in spinal cord, heart, kidney and RT. However, in liver only DHT competed significantly (P less than 0.01) for binding. This difference in binding of DHT vs T in the liver was further investigated by incubating liver and kidney cytosols with [3H]DHT and [3H]T at 4 degrees C. We identified the metabolic products by mobility on Sephadex LH-20 columns and reverse isotope dilution. Liver cytosols metabolized [3H]DHT to 5 alpha-androstane- 3 alpha,17 beta-diol (5 alpha-diol) and [3H]T to 5 beta-androstane-3 alpha, 17 beta-diol (5 beta-diol) at 4 degrees C. In contrast, kidney cytosols metabolized [3H]DHT while [3H]T remained unchanged. Further studies indicated that a 50-fold molar excess of 5 alpha-diol inhibited the binding of [3H]R1881 in liver cytosols by about 50% whereas the same molar concentration of 5 beta-diol had no effect. These data demonstrate the presence of AR in peripheral tissues of fetal rhesus monkeys and suggest that androgens through their receptors may affect development of these tissues. Liver cytosols are capable of metabolizing T and DHT at 4 degrees C at conditions similar to those used for measuring cytosolic AR. However, T and DHT are metabolized differently, generating different isomers which have different affinities for hepatic AR.

Androgens↗
PubMed1977

The distribution of methionine-enkephalin and leucine-enkephalin in the brain and peripheral tissues.

1 A method is described for the rapid extraction of opioid peptides from the brain and other tissues. The method is based on acid extraction of tissues followed by adsorption of the extract onto Amberlite XAD-2 resin. Elution with methanol separates the enkephalins and alpha-endorphin from beta-endorphin.2 Over 90% of the opioid peptide activity isolated from brain and gut of several species by our method was due to methionine- and leucine-enkephalin. In contrast, the major opioid peptide activity recovered from the pituitary was due to peptides of much greater mol. wt. than the enkephalins.3 An opioid peptide with properties unlike those of the known endorphins or enkephalins was present in brain extracts. This peptide, termed epsilon-endorphin, has an apparent mol. wt. of 700 to 1200; it constituted between 5 to 10% of the total opioid activity in our extracts.4 A differential assay of methionine- and leucine-enkephalin was made either by destroying methionine-enkephalin activity with cyanogen bromide or by separating the peptides by thin layer chromatography.5 The ratio of methionine-enkephalin to leucine-enkephalin varied greatly in different brain regions. The highest proportions of leucine-enkephalin were found in the cerebral cortex and hippocampus.6 Formaldehyde perfusion and fixation of the brain in vivo had no significant effect on the brain content of enkephalin, indicating that proteolytic breakdown is not a major problem in the extraction of these peptides.7 It is suggested that the enkephalins may have a neurotransmitter role in both brain and peripheral tissues and that methionine- and leucine-enkephalin may subserve separate neuronal functions.

Animals↗
PubMed2003

Adrenomedullin receptor binding sites in rat brain and peripheral tissues.

The existence of specific adrenomedullin receptor binding sites was investigated using the agonist peptide fragment [125I]human adrenomedullin-(13-52) in rat brain, lung and vas deferens homogenates. Saturation-binding experiments suggest that [125I]human adrenomedullin-(13-52) binds to an apparent single population of sites with similar affinities (K(D) of 0.3 to 0.6 nM) but with different maximal binding capacity in the rat brain, lung and vas deferens homogenates (B(max) of 73, 1760 and 144 fmol/mg protein, respectively). Competition-binding experiments using various analogues and fragments of calcitonin gene-related peptide (CGRP) and adrenomedullin were also performed using this radioligand. Competition-binding profiles suggest the possible existence of heterogeneous populations of adrenomedullin receptor binding sites. For example, in rat brain, human adrenomedullin-(1-52) and human adrenomedullin-(13-52) competed against specific [125I]human adrenomedullin-(13-52) sites with competition curves best fitted to a two-site model. Additionally, human calcitonin gene-related peptide alpha (hCGRPalpha), [Cys(Et)(2,7)]hCGRPalpha and [[R-(R,(R*,S*)]-N-[2-[[5-amino-1-[[4-(4-pyridinyl)-1-piperazinyl]carbonyl]pentyl]amino]-1-[(3,5-dibromo-4-hydroxyphenyl)methyl]-2-oxoethyl]-4-(1,4-dihydro-2-oxo-3(2H)-quinazolinyl)-,1-Piperidinecarboxamide] (BIBN4096BS) competed against specific [125I]human adrenomedullin-(13-52) binding with profiles that were also best fitted to a two-site model. Furthermore, binding assays performed in the presence of GTPgammaS (100 microM) revealed that this compound inhibited 20% of specific [125I]human adrenomedullin-(13-52) sites in rat brain homogenates and competition curves of human adrenomedullin-(1-52) and [Cys(Et)(2,7)]hCGRPalpha against specific [125I]human adrenomedullin-(13-52) sites remained best fitted to a two-site model. Moreover, the existence of specific [125I]human adrenomedullin-(13-52) binding sites that are resistant to human adrenomedullin-(22-52) and human CGRP-(8-37) is suggested in the rat brain and vas deferens. Taken together, these data provide evidence for the possible existence of heterogeneous populations of adrenomedullin binding sites in rat brain and peripheral tissues.

Adrenomedullin↗
PubMed1997

Molecular cloning of rat G-protein-coupled receptor kinase 6 (GRK6) from brain tissue, and its mRNA expression in different brain regions and peripheral tissues.

The rat G-protein-coupled receptor kinase 6 (GRK6) cDNA was cloned from rat brain tissue by a combination of reverse-transcription polymerase chain reactions (RT-PCR), based on homology to the cloned human GRK6, and rapid amplification of cDNA ends (RACE-PCR). We obtained a clone of 2817 bp with an open reading frame of 1731 bp encoding for a protein of 576 amino acids that is 96.7% identical and 97.9% similar to its human counterpart. mRNA was detectable in all brain areas examined. In addition, GRK6 was expressed in skeletal muscle, small intestine, aorta, liver, heart, lung, thymus, stomach, uterus and kidney.

Amino Acid Sequence↗
PubMed1985

Apolipoprotein E synthesis in peripheral tissues of nonhuman primates.

The tissue distribution of apolipoprotein (apo) E synthesis in the cynomolgus monkey, Macaca fascicularis, was determined via short-term organ culture with radiolabeled amino acid. Tissue extracts were reacted with antiserum to apo-E, and immunoprecipitates were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Newly synthesized apo-E was detected in liver, adrenal, testis, lung, spleen, mesenteric lymph node, and kidney. Peripheral and hepatic apo-E showed the same electrophoretic mobility. High resolution two-dimensional gel analysis showed that newly synthesized apo-E exists in two major isoforms in each tissue examined. Comparison of isoform patterns and mixing experiments showed that newly synthesized apo-E isoforms have identical charge properties in each tissue examined. These data indicate that numerous peripheral tissues synthesize apo-E that is indistinguishable from liver apo-E by the criteria tested. Measurements of relative synthetic capacities illustrate that apo-E is a moderately abundant protein product of a variety of peripheral tissues although quantitative differences in apo-E synthesis occur. Apo-E mRNA from cynomolgus monkey liver and human Hep G2 cells co-migrated with an electrophoretic mobility corresponding to approximately 1200 nucleotides. Apo-E mRNA from liver, brain, thymus, kidney, testis, lymph node, and spleen was the same size. Primer extension analysis yielded a cDNA product representing complete copying of the 5' untranslated region of human Hep G2 apo-E mRNA. A cDNA of identical size was produced with cynomolgus monkey apo-E mRNA from liver, spleen, brain, lymph node, kidney, lung, and thymus. These data suggest that transcription of the apo-E gene is initiated at or near the same site in each tissue examined.

Adrenal Cortex↗
PubMed1999

Role of the sympathetic nervous system and insulin in enhancing glucose uptake in peripheral tissues after intrahypothalamic injection of leptin in rats.

Our previous study demonstrated that microinjection of leptin into the ventromedial hypothalamus (VMH) dramatically increased glucose uptake in the heart, brown adipose tissue (BAT), and skeletal muscles, but not in white adipose tissue (WAT) in conscious unrestrained rats, as assessed in vivo by the 2-[3H]deoxyglucose method. Here we examined the role of the sympathetic nervous system and insulin in enhanced glucose uptake by tissues after hypothalamic leptin injection. Pretreatment with guanethidine significantly suppressed the increased glucose uptake by the tissues in response to leptin injected into the VMH, whereas bilateral adrenal demedullation had no significant effect. Treatment with propranolol but not phenoxybenzamine also decreased significantly enhanced glucose uptake by the tissues. We further examined the interaction of the effects of hypothalamic leptin and insulin administered peripherally by clamping the glucose concentrations at a constant level. When leptin was injected into the VMH and a maximal dose of insulin was administered intravenously, the rates of glucose uptake by the heart, BAT, and skeletal muscles, but not by WAT, markedly increased beyond the values reached by insulin stimulation alone. Surgical sympathetic denervation of BAT abolished the enhancement of glucose uptake in this tissue, decreasing to the level stimulated by insulin alone. These results appear to indicate that leptin in the hypothalamus enhances glucose uptake in certain peripheral tissues through mediation of a beta-adrenergic mechanism for the sympathetic nerves innervating the tissues and that central leptin and peripheral insulin have a synergistic role in augmenting tissue glucose uptake.

Adipose Tissue↗
PubMed2001

Prepro-orexin and orexin receptor mRNAs are differentially expressed in peripheral tissues of male and female rats.

Orexins are produced specifically by neurons located in the lateral hypothalamus. Recent results suggested peripheral actions of orexins. Therefore, we analyzed the mRNA expression of prepro-orexin and the orexin receptor subtypes OX(1) and OX(2) in peripheral rat tissues. Using real-time quantitative RT-PCR we detected significant amounts of prepro-orexin mRNA in testis, but not in ovaries. OX(1) receptor mRNA was highly expressed in the brain and at lower levels in the pituitary gland. Only small amounts of OX(1) receptor mRNA were found in other tissues such as kidney, adrenal, thyroid, testis, ovaries, and jejunum. Very high levels of OX(2) receptor mRNA, 4-fold higher than in brain, were found in adrenal glands of male rats. Low amounts of OX(2) receptor mRNA were present in lung and pituitary. In adrenal glands, OX(2) receptor mRNA was localized in the zona glomerulosa and reticularis by in situ hybridization, indicating a role in adrenal steroid synthesis and/or release. OX(1) receptor mRNA in the pituitary and OX(2) receptor mRNA in the adrenal gland were much higher in male than in female rats. In the hypothalamus, OX(1) receptor mRNA was slightly elevated in female rats. The differential mRNA expression of orexin receptor subtypes in peripheral organs indicates discrete peripheral effects of orexins and the existence of a peripheral orexin system. This is supported by the detection of orexin A in rat plasma. Moreover, the sexually dimorphic expression of OX(1) and OX(2) receptors in the hypothalamus, pituitary, and adrenal glands suggests gender-specific roles of orexins in the control of endocrine functions.

Adrenal Glands↗
PubMed2002

Selective expression of prion protein in peripheral tissues of the adult mouse.

The level of expression of normal cellular prion protein, PrP(c) (cellular prion protein), controls both the rate and the route of neuroinvasive infection, from peripheral entry portal to the CNS. Paradoxically, an overview of the distribution of PrP(c) within tissues outside the CNS is lacking. We have used novel antibodies that recognise cellular prion protein in glutaraldehyde-fixed tissue (in order to optimise immunohistochemical labelling of this conformationally labile protein), in combination with in situ hybridisation, to examine the expression of PrP(c) in peripheral tissues of the adult mouse. We found that although prion protein is expressed in many tissues, it is expressed at high levels only in discrete subpopulations of cells. Prominent amongst these are elements of the "hardwired neuroimmune network" that integrate the body's immune defence and neuroendocrine systems under CNS control. These prion protein-expressing elements include small diameter afferent nerves in the skin and the lamina propria of the aerodigestive tract, sympathetic ganglia and nerves, antigen presenting and processing cells (both follicular and non-follicular dendritic cells) and sub-populations of lymphocytes particularly in skin, gut- and bronchus-associated lymphoid tissues. Prion protein is also expressed in the parasympathetic and enteric nervous systems, in the dispersed neuroendocrine system, and in peripheral nervous system axons and their associated Schwann cells. This selective expression of cellular prion protein provides a variety of alternative routes for the propagation and transport of prion infection entering from peripheral sites, either naturally (via the aerodigestive tract or abraded skin) or experimentally (by intraperitoneal injection) to the brain. Key regulatory cells that express prion protein, and in particular enteroendocrine cells in the mucosal wall of the gut, and dendritic cells that convey pathogens from epithelial layers to secondary lymphoid organs, may be particularly important in the transmission of infection in the periphery.

Animals↗