| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
ARTICLE |
Department of Neurobiology (C.F.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary 1083; Tupper Research Institute and Department of Medicine (S.S., R.M.L.), Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine, Tufts-New England Medical Center, Boston, Massachusetts 02111; Departments of Community Health (W.M.R.) and Neuroscience (R.M.L.), Tufts University School of Medicine, Boston, Massachusetts 02111; Thyroid Division (J.W.H., A.C.B.), Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts 02115; and Department of Medicine (C.H.E.), Division of Endocrinology, University of Massachusetts Medical School, Worcester, Massachusetts 01655
Address all correspondence and requests for reprints to: Ronald M. Lechan, M.D., Ph.D., Professor of Medicine, Division of Endocrinology, Box No. 268, Tufts-New England Medical Center, 750 Washington Street, Boston, Massachusetts 02111. E-mail: rlechan{at}lifespan.org.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-MSH has a potent stimulatory action on hypophysiotropic TRH synthesizing neurons in the hypothalamic paraventricular nucleus (PVN), preventing the effects of fasting on the gene expression of the TRH prohormone (proTRH), we hypothesized that agouti-related protein (AGRP), a melanocortin receptor antagonist, may exert a central inhibitory action on these neurons. To test the hypothesis, the effects of intracerebroventricularly administered AGRP on circulating thyroid hormone levels and proTRH mRNA in the hypothalamic paraventricular nucleus (PVN) were compared with the effects of the recently described central inhibitor of the HPT axis, neuropeptide Y (NPY). AGRP administration increased food consumption and weight gain, suppressed circulating levels of thyroid hormones (T3 and T4), and resulted in an inappropriately normal TSH. These alterations were associated with a significant suppression of proTRH mRNA in the PVN, indicating that AGRP infusion resulted in a state of central hypothyroidism. While similar observations were made in the NPY-infused animals, AGRP-treated animals had higher feeding efficiency, higher T4 levels, and lower type 2 iodothyronine deiodinase levels in brown adipose tissue than NPY-infused animals. These data demonstrate that AGRP and NPY have a similarly potent inhibitory action on the proTRH gene expression of hypophysiotropic neurons, indicating that both AGRP and NPY may play a major role in the inhibition of the HPT axis during fasting. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
One peptide of arcuate nucleus origin that may have an important role in leptin-regulated modulation of the HPT axis is a proopiomelanocortin (POMC)-derived peptide, -MSH (6). This concept is based in the knowledge that -MSH is synthesized in arcuate nucleus neurons that express leptin receptors (7), show a reduction in POMC mRNA when leptin levels are suppressed during fasting (8), send monosynaptic projections to the soma and first-order dendrites of TRH neurons in the PVN (6), and when administered exogenously by intracerebroventricular (icv) infusion, can completely restore fasting levels of proTRH mRNA in the PVN to normal fed levels, despite continuation of the fast (6). In addition to -MSH, however, the potent orexigenic peptide, agouti-related protein (AGRP), is also contained in axon terminals heavily innervating TRH-producing neurons in the PVN (6, 9) and, in fact, are juxtaposed to all TRH neurons receiving an -MSH innervation (6). AGRP- and -MSH-containing axons derive from separate populations of neurons in the arcuate nucleus that are inversely regulated by leptin (10, 11). Because AGRP exerts its biological effects by acting as a competitive antagonist or inverse agonist at melanocortin receptors (12, 13, 14), it is conceivable that during fasting, an increase in AGRP cooperates in the inhibition of the TRH gene by antagonizing the action of -MSH at melanocortin receptors. To test this hypothesis, we determined whether the central administration of AGRP to fed animals replicate the response of the HPT axis observed during fasting. Because NPY has been recently shown to have a potent inhibitory effect on TRH neurons in ad libitum fed animals (15), the effect of centrally administered AGRP was compared with the effect of centrally administered NPY.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Animal preparation for AGRP infusion
Adult rats were implanted with a 22-gauge stainless steel guide cannula (Plastics One Inc., Roanoke, VA) into the lateral cerebral ventricle under stereotaxic control (coordinates from Bregma AP -0.8; Lat 1.2 D-Vent 3.2) through a burr hole in the skull. The cannula was secured to the skull with three stainless steel screws and dental cement and temporarily occluded with a dummy cannula. Bacitracin ointment was applied daily to the interface of the cement and the skin. One week after icv cannulation, under general anesthesia, an osmotic minipump (Alzet Model 1003D, Alza Pharmaceuticals, Palo Alto, CA) was implanted intradermally between the scapulas and connected with PE tubing to a 28-G needle that was permanently inserted into and extended 1 mm below the external guide cannula. The animals had free access to food and were divided in three groups. The osmotic minipumps delivered artificial cerebrospinal fluid (a-CSF) (140 mM NaCl; 3.35 mM KCl; 1.15 mM MgCl2; 1.26 mM Ca Cl2; 1.2 mM Na2HPO4; 0.3 mM NaH2PO4; 0.1% BSA, pH 7.4) (group 1, n = 8), 5.67 µg/24 h AGRP (83–132) (Phoenix Pharmaceuticals, Inc., Belmont, CA) in a-CSF (group 2, n = 6), or 10 µg/24 h NPY (Peninsula Laboratories, Inc., Belmont, CA) (group 3, n = 7) for 3 d at a rate of 1 µl/h. These doses have been previously shown to induce pronounced orexigenic activity when administered centrally (15, 16). The weight of the animals and food intake were monitored daily.
At the completion of the experiment, the animals were anesthetized with sodium pentobarbital between 0900 and 1200 h, brown fat was dissected from the cervical region, blood taken from inferior vena cava for measurement of serum T4, T3, TSH, and leptin, and the animals immediately perfused with fixative as described below. Blood was collected into polypropylene tubes, centrifuged for 15 min at 4000 rpm, and the plasma stored at -80 C until assayed. The cervical brown fat was then snap frozen in dry ice and stored at -70 C until processed for D2 enzymatic activity, and uncoupling protein (UCP)-1, spot 14, and triglyceride levels. Brown adipose tissue was carefully dissected from the interscapular area and white fat dissected from the epididymal fat pad and weighed.
Tissue preparation for in situ hybridization histochemistry
Under sodium pentobarbital anesthesia, the animals were perfused transcardially with 20 ml 0.01 M PBS (pH 7.4), containing 15,000 U/liter heparin sulfate followed by 150 ml 4% paraformaldehyde in PBS. The brains were removed and postfixed by immersion in the same fixative for 2 h at room temperature. Tissue blocks containing the hypothalamus were cryoprotected in 20% sucrose in PBS at 4 C overnight, then frozen on dry ice. Serial 18-µm-thick coronal sections through the rostrocaudal extent of the PVN were cut on a cryostat (Leica CM 3050 S, Nussloch, Germany) and adhered to Superfrost/Plus glass slides (Fisher Scientific Co., Pittsburgh, PA) to obtain four sets of slides, each set containing every fourth section through the PVN. Cannula placement was confirmed by light microscopic examination. The tissue sections were desiccated overnight at 42 C and stored at -80 C until prepared for in situ hybridization histochemistry.
In situ hybridization histochemistry
Every fourth section of the PVN was hybridized with a 1241-bp single stranded [35S]-uridine triphosphate-labeled cRNA probe for pro-TRH as previously described (17, 18). The hybridizations were performed under plastic coverslips in a buffer containing 50% formamide, a 2-fold concentration of standard sodium citrate (2x SSC), 10% dextran sulfate, 0.5% sodium dodecyl sulfate, 250 µg/ml denatured salmon sperm DNA, and 6 x 105 cpm of radiolabeled probe for 16 h at 56 C. Slides were dipped into Kodak NTB2 autoradiography emulsion (Eastman Kodak Co., Rochester, NY), and the autoradiograms were developed after 6 d of exposure at 4 C.
Image analysis
Autoradiograms were visualized under darkfield illumination using a COHU 4910 video camera (COHU, Inc., San Diego, CA). The images were analyzed with a Macintosh G4 computer using Scion Image. Background density points were removed by thresholding the image and integrated density values (density x area) of hybridized neurons in the same region of each side of the PVN were measured in six consecutive sections for each animal. Nonlinearity of radioactivity in the emulsion was evaluated by comparing density values with a calibration curve created from autoradiograms of known dilutions of the radiolabeled probes immobilized on glass slides in 1.5% gelatin fixed with 4% formaldehyde, and exposed and developed simultaneously with the in situ hybridization autoradiograms.
Hormone measurements
Serum T4, T3, and TSH concentrations were measured by RIA as previously described (19). Materials for the TSH RIA were provided by the NIDDK National Hormone and Pituitary Program (Baltimore, MD) using NIDDK rat TSH RP-2 as the standard. Specific antisera for T4 and T3 were obtained from Ventrex (Portland, ME). The labels, [125I]-T4 and [125I]-T3 for the T4 and T3 assays, respectively, were obtained from NEN Life Science Products (Boston, MA). Serum leptin was measured by RIA using a rat leptin kit RL83K from Linco Research, Inc. (St. Charles, MO). The detection limit was 0.25 ng/ml and the ED50 was 3.38 ng/ml. The Cobra 500 program was used for data reduction and calculation of the RIA results.
Brown adipose tissue measurements
D2 activity was measured as described (20). Approximately 250 µg total brown adipose tissue lysate protein was incubated for 2 h in the presence of 1 nM [125I]5'-T4, 20 mM dithiothreitol, and 1 mM propylthiouracil (PTU). Specific T4 to T3 conversion was calculated by subtracting nonspecific deiodination in tubes containing the same amount of lysate protein obtained from human embryonic kidney cells. The background activity of these samples was less than 2%. Deiodinase activity was expressed as fmol T4/min·mg protein and as total D2 activity in brown adipose tissue. Triglyceride content was measured in brown adipose tissue fragments after samples were dried and saponified. Results were expressed per milligram of wet weight (21). Spot14 mRNA levels were measured by Northern blot. BAT fragments were processed for RNA extraction using TRIzol Reagent according to the instructions of the manufacturer (Life Technologies, Inc., Grand Island, NY). Northern analysis was performed using 10 µg RNA per lane and a full-length mouse spot14 cDNA, kindly provided by Dr. Carry N. Mariash (University of Minnesota, Minneapolis, MN). Levels were normalized for 28S ribosomal RNA, stained by ethidium bromide. Mitochondrial UCP-1 levels were measured in samples of cervical brown fat by Western blot after 5 µg total mitochondrial protein were resolved in a 12% SDS-PAGE and electrotransferred to a polyvinylidene difluoride membrane (21). Anti-UCP-1 antiserum was a gift from Dr. J. Enrique Silva (Jewish General Hospital, Montréal, Québec, Canada) and used at 1:2000 dilution.
Statistical analysis
Results are presented as means ± SE (SEM). Due to technical complexities of the assays, sample sizes often differed for the various variables. It is assumed that the data that were analyzed represent a random selection of the animals in the study. While no data were excluded from the analyses, because of the small sample sizes, data were visually examined for skewness and potential outliers and the more conservative nonparametric analyses used whenever the normality of the distribution was in question. As a result, the TSH data were analyzed by the Kruskal-Wallis and Mann-Whitney tests. In all other cases, groups were compared with one-way ANOVA followed by Newman-Keuls post hoc testing. All data were entered into and analyzed using SPSS, Inc., version 10.1. P values are presented, a level less than 0.05 was considered statistically significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
shows the food intake, weight gain, weight of brown and white fat, parameters of brown adipose tissue activity, and the results of hormone determinations. AGRP-treated animals consumed significantly more food than controls during the 3 d of infusion but ate less than the NPY-treated animals. The weight gain of both AGRP- and NPY-treated animals was similar, however, and approximately 200% of the weight gain of controls. The weight of the interscapular brown fat of AGRP- administered animals was intermediate between the controls and NPY-treated animals, but in both groups, the characteristic deep reddish-brown color of this tissue changed to a light tan or white color. The weight of the epididymal fat pad, however, did not increase in the AGRP-treated animals, whereas it increased significantly following NPY treatment. D2 activity in brown fat was not significantly increased in the AGRP group compared with the control group, whereas a significant increase compared with both control and AGRP-treated groups was observed after NPY treatment. The triglyceride content was significantly increased in brown adipose tissue fragments of both AGRP- and NPY-treated animals. This prompted us to evaluate brown adipose tissue lipogenesis by measuring spot14 mRNA levels, a lipogenic-related protein (22). The Northern analysis revealed that spot 14 mRNA levels were markedly increased in the brown adipose tissue of the AGRP- and NPY-treated animals, indicating increased lipogenesis. The brown adipose tissue thermogenic potential was also evaluated by measuring mitochondrial UCP-1 levels, which was found to be significantly increased in both AGRP- and NPY-treated groups compared with controls, but not significantly different from each other (Table 1). This experiment was repeated a second time and found to be consistent with the first experiment, showing UCP-1 levels in the AGRP group increasing 2.5 ± 0.1-fold over control values and in the NPY group increasing 2.3 ± 0.5-fold over control values (Fig. 1) as compared with a 1.9 ± 0.2-fold increase for AGRP and 2.1 ± 0.1-fold increase in the first experiment.
|
|
The leptin values showed significant differences from their control values in both the AGRP and NPY experimental groups. However, significant differences were also apparent between the leptin levels of the NPY and AGRP groups, with the AGRP group having an intermediate value between the NPY group and controls.
Effect of AGRP and NPY administration on proTRH mRNA in the PVN
In control animals, neurons containing proTRH mRNA were readily visualized by in situ hybridization histochemistry, symmetrically distributed in the medial and periventricular parvocellular subdivisions of the PVN on either side of the third ventricle (Fig. 2A). AGRP caused a marked reduction in the hybridization signal over paraventricular proTRH neurons (Fig. 2B), similar to that observed for NPY (Fig. 2C). By image analysis, the sum of integrated density values of proTRH mRNA in the PVN of AGRP-treated animals was reduced by approximately 60% compared with the control animals (Fig. 3) and not significantly different than that observed in the NPY-treated animals. The effect of both AGRP and NPY to reduce proTRH mRNA was selective to neurons in the PVN, as proTRH-producing neurons in the adjacent lateral hypothalamus showed no apparent reduction in silver grain accumulation (Fig. 4).
|
|
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-MSH, the melanocortin signaling system also includes AGRP (12). AGRP acts as a competitive antagonist to -MSH at melanocortin receptors (12) and has both orexigenic and weight promoting properties (12). Because AGRP is regulated inversely to -MSH by leptin (8, 26), the increase in AGRP with fasting most likely participates in the down-regulation of melanocortin signaling by antagonizing the action of -MSH, concurrently with inhibition of the POMC gene.
Previous studies from our laboratory suggested that at least one of the mechanisms whereby fasting causes central hypothyroidism by reducing proTRH gene expression in the hypothalamic PVN is the inhibition of -MSH synthesis (6). Centrally administered -MSH to fasting animals was shown to exert a potent stimulatory effect on the transcription of the TRH gene in hypophysiotropic neurons, completely overcoming the inhibitory effect of fasting despite continuation of the fast (6). Because AGRP-containing axons densely innervate the hypophysiotropic TRH neurons (6, 9), it seemed likely that AGRP, acting as an antagonist to -MSH, may also contribute to the inhibitory action of fasting on the HPT axis. Earlier observations demonstrating that AGRP administration in vivo decreases TSH levels and in vitro prevents -MSH- and leptin-induced TRH release from hypothalamic explants (27), further supported this hypothesis. To determine whether AGRP has an inhibitory effect on TRH gene expression in hypophysiotropic neurons of the hypothalamic PVN, we administered AGRP continuously into the lateral ventricle of ad libitum fed animals and determined the effect on circulating thyroid hormone levels and the concentration of proTRH mRNA.
AGRP treatment significantly increased food intake and weight gain compared with animals receiving a-CSF, in keeping with the role of AGRP to promote energy conservation (16) and establishing the biologic activity of exogenously administered AGRP in these animals. While no increase in the weight of the epididymal fat pad was observed, a longer duration of the AGRP infusion than 3 d may have been required to replicate the earlier data by Small et al. (16).
Circulating thyroid hormone levels were significantly reduced with T4 approximately 50% of control values and T3 approximately 40% of control values in the AGRP-treated animals. Although TSH was not significantly different in the AGRP-treated animals compared with controls, because the HPT axis is regulated by an inverse feedback mechanism by circulating levels of thyroid hormone (17), the absence of a TSH rise in the presence of the significant decline in circulating thyroid hormone levels is consistent with central hypothyroidism (28). This was due to a potent inhibitory effect of AGRP on proTRH gene expression in PVN neurons, reducing proTRH mRNA more than 60% of control values. The T3/T4 ratio in the AGRP-treated animals, however, was similar to controls, but markedly increased in the NPY-treated group, suggesting that, unlike AGRP, NPY causes an increase in iodothyroine deiodinase activity, an enzyme that converts T4 to biologically active T3 (29). Indeed, while total D2 activity in brown adipose tissue in the AGRP-treated group was increased, it was not significantly different than the controls, whereas NPY treatment resulted in a significant, more than 7-fold increase in D2 activity, which was significantly greater than the value in the AGRP-treated group. Given the rise in D2 activity in brown adipose tissue of the NPY-treated animals and the importance of this tissue to plasma T3 in rodents (30), we presume that increased conversion of T4 to T3 in brown adipose tissue was responsible for the increased T3/T4 ratio in the NPY-treated group. The rise in D2 activity in the NPY-treated group is most likely secondary to the marked fall in T4 in these animals (31), although direct effects of the increased levels of leptin in the circulation on D2 activity might also be a factor that has not yet been explored.
As all TRH neurons in the medial parvocellular subdivision of the PVN were uniformly inhibited by AGRP, it is likely that the vast majority of these neurons express melanocortin receptors. This possibility is further supported by the ability of icv administered -MSH to induce the phosphorylation of cAMP response element binding protein (CREB) in more than 80% of proTRH neurons in the medial parvocellular PVN (32), assuming that CREB phosphorylation is an important initial step in -MSH-mediated regulation of the TRH gene. Nevertheless, only approximately 40% of TRH neurons in the PVN contain melanocortin type 4 receptor mRNA (33), and only 34% of TRH neurons in the medial parvocellular PVN receive contacts by axon terminals containing -MSH (6). While technical considerations may explain this discrepancy, the possibility that TRH neurons may express melanocortin type 3 receptors should also be considered. Further, while AGRP acts as an antagonist to -MSH at melanocortin receptors, recent data by Nijenhuis et al. (13) and Haskell-Luevano and Monck (14) have shown that melanocortin receptors have inherent basal activity. Thus, innervation of neurons expressing melanocortin receptors by axons containing -MSH may not be absolutely necessary for melanocortin signaling. Because all TRH neurons in the PVN are innervated by axons containing AGRP (9), it is conceivable that regulation of the TRH gene in hypophysiotropic neurons is largely mediated by AGRP and not -MSH.
The molecular mechanisms whereby AGRP may inhibit TRH gene expression is suggested by Harris et al. (33), showing that -MSH-induced activation of the TRH promoter is dependent upon a multifunctional cAMP response element in the TRH gene that also binds the thyroid hormone receptor (34). By deleting the cAMP response element, most of the -MSH-induced stimulation could be prevented and basal activity dramatically lowered (33). In addition, cotransfecting a mutant version of CREB, which cannot be phosphorylated by PKA, together with the TRH promoter in a heterologous cell system, significantly reduced stimulation by -MSH (33). Thus, by preventing -MSH from phosphorylating CREB, the inhibitory feedback effect of thyroid hormone bound to its receptor on the TRH gene may become enhanced due to reduced competition by lower intranuclear concentrations of phosphoCREB.
The ability of AGRP to inhibit proTRH gene expression in hypophysiotropic neurons in the PVN was similar to that of NPY, both causing a selective, approximately 60% reduction of proTRH hybridization signal in the PVN compared with the controls. NPY, however, had a more potent effect on reducing peripheral T4 levels than AGRP, raising the possibility that NPY has additional effects on the HPT axis downstream from transcriptional regulation of the TRH gene. One possibility to explain this difference is the effect of these two peptides on corticosterone secretion. NPY densely innervates CRH-producing neurons in the PVN (35) and is known to increase corticosterone (36), whereas AGRP has little innervation of CRH neurons (37) and has no effect on corticosterone secretion (16), suggesting a minimal role in HPA axis regulation. Thus, increasing circulating corticosterone concentrations may be responsible for the additional effect of NPY on the HPT axis to even further reduce the level of biologically active TSH (38). Increased corticosterone levels in the NPY-infused animals may also explain the apparent greater feeding efficiency of the AGRP- compared with the NPY-treated animals. While the AGRP-treated animals ate significantly less food than the NPY-treated animals, both groups gained a similar amount of weight, perhaps due to the effect of corticosterone to increase muscle proteolysis (39), effectively decreasing lean body mass. Because both AGRP and NPY have equally potent activity to inhibit the TRH gene, it is possible that with the exception of peripheral effects of NPY on T4, these peptides serve a redundant rather than cooperative function. This concept would be in keeping with the observations that the NPY knockout mouse retains normal thyroid function and shows a reduction in circulating thyroid hormone levels in response to fasting (40). No significant effect on the HPT axis might also be expected with selective AGRP deficiency, provided NPY remains intact. This is based on studies demonstrating that mutation of the melanocortin type 4 receptor in patients with morbid obesity has no effect on the thyroid hormone levels (41) and that NPY can antagonize the stimulatory effects of -MSH (42) (Sarkar, S., and R. M. Lechan, unpublished observations).
An interesting additional observation in this study was the effect of both AGRP and NPY to significantly increase UCP-1 in brown adipose tissue, contrary to what might have been expected (16, 43). UCP-1, a mitochondrial protein encoded by a cAMP-dependent gene, generally reflects the activity of this tissue (44, 45) and was measured as an index of the biological activity of the infused AGRP and NPY. While fasting is known to reduce UCP-1 mRNA in brown adipose tissue (46), we presume that the elevation in UCP-1 protein observed in our study in response to the exogenous administration of AGRP and NPY administration was secondary to the rise in plasma leptin (46), normally suppressed by fasting (3). In this regard, it is important to note that UCP1 per se does not catalyze mitochondrial uncoupling. Unless the adrenergic-signaling pathway is activated and lipolysis is increased in the brown adipose tissue, energy expenditure will remain low, regardless of the UCP-1 mitochondrial concentration (47). In fact, other experimental situations in which there is disassociation between UCP-1 levels in brown adipose tissue and energy expenditure due to poor adrenergic responsiveness in the brown adipocytes have been reported (21, 47, 48). These include mice with targeted disruption of the Dio2 gene, in which UCP-1 is normal but cAMP generation is not (21), and GC-1-treated hypothyroid mice, a thyroid hormone receptor ß selective agonist that restores UCP-1 gene expression but not adrenergic signaling (48). Disassociation between the level of UCP-1 and mitochondrial uncoupling is further confirmed in our animals by the increase in triglyceride levels in brown adipose tissue of the AGRP- and NPY-treated groups, indicative that lipolysis had not taken place, presumably due to suppression of the sympathetic nervous system by AGRP and NPY (49). The increased spot 14 mRNA levels, a marker for lipogenesis, and in triglyceride accumulation would explain the especially pale color of the brown adipose tissue in the experimental animals, in contrast to the more typical reddish color of stimulated brown adipose tissue observed during cold exposure (50).
We conclude that AGRP has a potent action on the HPT axis to inhibit proTRH mRNA in hypophysiotropic neurons in the PVN. As AGRP treatment closely replicates changes in the HPT axis observed during fasting and with NPY treatment, we propose that either AGRP or NPY may mediate the effects of fasting to induce central hypothyroidism.
|
Footnotes |
|---|
Abbreviations: a-CSF, Artificial cerebrospinal fluid; AGRP, agouti-related protein; CREB, cAMP response element binding protein; HPT, hypothalamic-pituitary-thyroid; icv, intracerebroventricular; NPY, neuropeptide Y; POMC, proopiomelanocortin; proTRH, TRH prohormone; PVN, paraventricular nucleus; UCP, uncoupling protein.
Received March 25, 2002.
Accepted for publication June 18, 2002.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-Melanocyte-stimulating hormone is contained in nerve terminals innervating thyrotropin-releasing hormone-synthesizing neurons in the hypothalamic paraventricular nucleus and prevents fasting-induced suppression of prothyrotropin-releasing hormone gene expression. J Neurosci 20:1550–1558-melanocyte-stimulating hormone. J Clin Endocrinol Metab 85:2596–2603-melanocyte stimulating hormone in vivo. Endocrinology 139:4428–4431-melanocyte stimulating hormone increases phosphorylation of CREB in TRH- and CRH-producing neurons of the hypothalamic paraventricular nucleus. Brain Res, in press
This article has been cited by other articles:
 |
|
 |
|
  E. Sanchez, P. S. Singru, R. Acharya, M. Bodria, C. Fekete, A. M. Zavacki, A. C. Bianco, and R. M. Lechan Differential Effects of Refeeding on Melanocortin-Responsive Neurons in the Hypothalamic Paraventricular Nucleus Endocrinology, September 1, 2008; 149(9): 4329 - 4335. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D C Ferguson, Z Caffall, and M Hoenig Obesity increases free thyroxine proportionally to nonesterified fatty acid concentrations in adult neutered female cats J. Endocrinol., August 1, 2007; 194(2): 267 - 273. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Voss-Andreae, J. G. Murphy, K. L. J. Ellacott, R. C. Stuart, E. A. Nillni, R. D. Cone, and W. Fan Role of the Central Melanocortin Circuitry in Adaptive Thermogenesis of Brown Adipose Tissue Endocrinology, April 1, 2007; 148(4): 1550 - 1560. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Fekete, P. S. Singru, E. Sanchez, S. Sarkar, M. A. Christoffolete, R. S. Riberio, W. M. Rand, C. H. Emerson, A. C. Bianco, and R. M. Lechan Differential Effects of Central Leptin, Insulin, or Glucose Administration during Fasting on the Hypothalamic-Pituitary-Thyroid Axis and Feeding-Related Neurons in the Arcuate Nucleus Endocrinology, January 1, 2006; 147(1): 520 - 529. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Stanley, K. Wynne, B. McGowan, and S. Bloom Hormonal Regulation of Food Intake Physiol Rev, October 1, 2005; 85(4): 1131 - 1158. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Coppola, R. Meli, and S. Diano Inverse Shift in Circulating Corticosterone and Leptin Levels Elevates Hypothalamic Deiodinase Type 2 in Fasted Rats Endocrinology, June 1, 2005; 146(6): 2827 - 2833. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Fekete, P. S. Singru, S. Sarkar, W. M. Rand, and R. M. Lechan Ascending Brainstem Pathways Are Not Involved in Lipopolysaccharide-Induced Suppression of Thyrotropin-Releasing Hormone Gene Expression in the Hypothalamic Paraventricular Nucleus Endocrinology, March 1, 2005; 146(3): 1357 - 1363. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A Cote-Velez, L Perez-Martinez, M Y Diaz-Gallardo, C Perez-Monter, A Carreon-Rodriguez, J-L Charli, and P Joseph-Bravo Dexamethasone represses cAMP rapid upregulation of TRH gene transcription: identification of a composite glucocorticoid response element and a cAMP response element in TRH promoter J. Mol. Endocrinol., February 1, 2005; 34(1): 177 - 197. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Wynne, S. Stanley, B. McGowan, and S. Bloom Appetite control J. Endocrinol., February 1, 2005; 184(2): 291 - 318. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Fekete, D. L. Marks, S. Sarkar, C. H. Emerson, W. M. Rand, R. D. Cone, and R. M. Lechan Effect of Agouti-Related Protein in Regulation of the Hypothalamic-Pituitary-Thyroid Axis in the Melanocortin 4 Receptor Knockout Mouse Endocrinology, November 1, 2004; 145(11): 4816 - 4821. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. M. Escobar, S. J. Krajewski, T. Sandoval-Guzman, M. L. Voytko, and N. E. Rance Neuropeptide Y Gene Expression Is Increased in the Hypothalamus of Older Women J. Clin. Endocrinol. Metab., May 1, 2004; 89(5): 2338 - 2343. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Guo, K. Bakal, Y. Minokoshi, and A. N. Hollenberg Leptin Signaling Targets the Thyrotropin-Releasing Hormone Gene Promoter in Vivo Endocrinology, May 1, 2004; 145(5): 2221 - 2227. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Zimmermann-Belsing and U. Feldt-Rasmussen Obesity: The New Worldwide Epidemic Threat to General Health and Our Complete Lack of Effective Treatment Endocrinology, April 1, 2004; 145(4): 1501 - 1502. [Full Text] [PDF]
|
|
|
|
 |
|
 T. Yasuda, T. Masaki, T. Kakuma, and H. Yoshimatsu Hypothalamic Melanocortin System Regulates Sympathetic Nerve Activity in Brown Adipose Tissue Experimental Biology and Medicine, March 1, 2004; 229(3): 235 - 239. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. C. Albarado, J. McClaine, J. M. Stephens, R. L. Mynatt, J. Ye, A. W. Bannon, W. G. Richards, and A. A. Butler Impaired Coordination of Nutrient Intake and Substrate Oxidation in Melanocortin-4 Receptor Knockout Mice Endocrinology, January 1, 2004; 145(1): 243 - 252. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Sarkar and R. M. Lechan Central Administration of Neuropeptide Y Reduces {alpha}-Melanocyte-Stimulating Hormone-Induced Cyclic Adenosine 5'-Monophosphate Response Element Binding Protein (CREB) Phosphorylation in Pro-Thyrotropin-Releasing Hormone Neurons and Increases CREB Phosphorylation in Corticotropin-Releasing Hormone Neurons in the Hypothalamic Paraventricular Nucleus Endocrinology, January 1, 2003; 144(1): 281 - 291. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Fekete, S. Sarkar, W. M. Rand, J. W. Harney, C. H. Emerson, A. C. Bianco, A. Beck-Sickinger, and R. M. Lechan Neuropeptide Y1 and Y5 Receptors Mediate the Effects of Neuropeptide Y on the Hypothalamic-Pituitary-Thyroid Axis Endocrinology, December 1, 2002; 143(12): 4513 - 4519. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||
