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Department of Neurobiology, Institute of Experimental Medicine, Hungarian Academy of Sciences (C.F.), Budapest 1083, Hungary; Tupper Research Institute and Department of Medicine, Division of Endocrinology, Diabetes, Metabolism, and Molecular Medicine (S.S., R.M.L.), 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, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School (J.W.H., A.C.B.), Boston, Massachusetts 02115; Department of Medicine, Division of Endocrinology, University of Massachusetts Medical School (C.H.E.), Worcester, Massachusetts 01655; and Institute of Biochemistry, University of Leipzig (A.B.-S.), Leipzig 04103, Germany
Address all correspondence and requests for reprints to: Ronald M. Lechan M.D., Ph.D., Division of Endocrinology, Box 268, Tufts-New England Medical Center, 750 Washington Street, Boston, Massachusetts 02111. E-mail: rlechan{at}lifespan.org.
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Introduction |
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Among the multiple actions of NPY to promote energy conservation is its effect on the hypothalamic-pituitary-thyroid (HPT) axis to induce a state of central hypothyroidism (1). When administered icv, NPY suppresses proTRH gene expression in hypophysiotropic neurons in the hypothalamic paraventricular nucleus (PVN), reducing circulating levels of TSH and thyroid hormones (T3 and T4) (1). This inhibitory action is presumed to occur directly on proTRH neurons in the PVN, because double-labeling immunocytochemical studies at the light and electron microscopic levels show dense innervation of TRH neurons by axons containing NPY (6), primarily of arcuate nucleus origin (7).
NPY binds to at least five different Gi protein-coupled receptors of the PP family, including the Y1, Y2, Y4, Y5, and Y6 receptors (8). However, NPY can exert its central effects only through the Y1, Y2, and Y5 receptors in the rat, as the Y6 receptor is not expressed in the rat (8), and NPY has negligible affinity for the Y4 receptor, which is primarily a PP receptor (8). Of these three NPY receptors, only the Y1 and Y5 receptor subtypes are believed to mediate the action of NPY on food intake (9, 10). Whether Y1 and Y5 receptors are also involved in mediating the inhibitory effects of NPY on the thyroid axis, however, is unknown. Broberger et al. (11) recently reported Y1 receptor-like immunoreactivity in TRH neurons in the PVN of the mouse, but it is unknown whether these neurons also express Y5 receptors and whether these receptors mediate the inhibitory effects of NPY on the HPT axis.
In the present studies we used newly developed, highly selective Y1 and Y5 receptor agonists (12, 13) to determine the importance of Y1 and Y5 receptors to inhibit the HPT axis in response to the central administration of NPY. One limitation of earlier in vivo studies using Y1 and Y5 receptor agonists was the lack of selectivity for a specific NPY receptor (12, 13). In contrast, the Y1 receptor agonist used in this study, [Phe7,Pro34]pNPY, has Y1 receptor preference of more than 3000-fold compared with the Y5 receptor and subnanomolar affinity to the Y1 receptor, but Ki values of approximately 30 nM for both Y2 and Y5 receptors (12). In addition, the Ala31, Aib32 (aminoisobutyric acid)-substituted selective Y5 receptor chimeric peptide, [chicken PP (cPP)1–7, NPY19–23, Ala31, Aib32, Q34]human PP (hPP), has more than 2000-fold higher affinity to Y5 receptors than to Y1 or Y2 receptors, more than 200-fold higher affinity than to the Y4 receptor (13), and a 50% inhibitory concentration of 0.24 nM for the Y5 receptor compared with more than 500 nM for the Y1 and Y2 receptors (13). Both Y1 and Y5 receptor agonists were either equivalent or more potent than NPY itself in inhibiting cAMP (12, 13).
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Materials and Methods |
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Animal preparation for NPY and NPY receptor agonist 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: anterior-posterior, -0.8; lateral, 1.2; dorsal-ventral, 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 was 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, an osmotic minipump (Alzet model 1003D, Alza Corp., Palo Alto, CA) was implanted under general anesthesia intradermally between the scapulas and connected with PE tubing to a 28-gauge needle that was permanently inserted into and extended 1 mm below the external guide cannula. The animals were divided into six groups. The first four groups had free access to food. The osmotic minipumps delivered artificial cerebrospinal fluid [aCSF; 140 mM NaCl, 3.35 mM KCl, 1.15 mM MgCl2, 1.26 mM Ca Cl2, 1.2 mM Na2HPO4, 0.3 mM NaH2PO4, and 0.1% BSA (pH 7.4); group 1; n = 8], 10 µg/24 h NPY in aCSF (group 2; n = 7), 10 µg Y1 receptor agonist ([Phe7,Pro34]pNPY) in aCSF (group 3; n = 8), or 5 µg Y5 receptor agonist ([cPP1–7, NPY19–23, Ala31, Aib32, Q34]hPP) in aCSF (group 4; n = 8) for 3 d at a rate of 1 µl/h. Two additional groups received the same dose of Y1 (group 5; n = 8) or Y5 (group 6; n = 8) receptor agonists but were pair-fed with the control group. The dose of NPY chosen in these studies has been previously shown to induce a pronounced orexigenic effect when administered centrally, associated with profound inhibition of the HPT axis (1). As the molecular weight and the affinity of the Y1 receptor agonist in vitro are similar to the activity of NPY (12), the Y1 receptor agonist was administered at the same dose as NPY. The Y5 receptor agonist was administered in a lower dose due to its approximately 2-fold greater affinity for Y5 receptors in vitro compared with NPY (13). The weights of the animals and food intakes 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 was taken from the inferior vena cava for measurement of serum T4, T3, TSH, and leptin, and the animals were immediately perfused with fixative as described below. Blood was collected into prolypropylene tubes and centrifuged for 15 min at 4000 rpm, and the plasma was stored at -80 C until assayed. Cervical brown adipose tissue (BAT) was carefully dissected from the interscapular area, and white fat was dissected from the epididymal fat pad and weighed. The cervical brown fat was then snap-frozen in dry ice and stored at -80 C until processed for D2 enzymatic activity and uncoupling protein-1 (UCP-1) levels.
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 and the arcuate nucleus were cut on a cryostat (Leica CM3050 S, Leica Microsystems, Nussloch GmbH, Germany) and adhered to SuperFrost Plus glass slides (Fisher Scientific, 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 were 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]UTP-labeled cRNA probe for proTRH as previously described (14, 15). Hybridization was performed under plastic coverslips in a buffer containing 50% formamide, a 2-fold concentration of standard sodium citrate, 10% dextran sulfate, 0.5% sodium dodecyl sulfate, 250 µg/ml denatured salmon sperm DNA, and 6 x 105 cpm 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 (Apple Computers, Cupertino, CA) using Scion Image (Scion Corp., Frederick, MD). 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 (16). 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, Linco Research, Inc., St. Charles, MO). The detection limit was 0.22 ng/ml, and the 50% effective concentration was 3.6 ng/ml. The Cobra 500 program (Perkin Elmer, Boston, MA) was used for data reduction and calculation of the RIA results.
BAT measurements
D2 activity was measured as previously described (17). Approximately 250 µg total brown adipose tissue lysate protein were incubated for 2 h in the presence of 1 nM [125I]5'T4, 20 mM dithiothreitol, and 1 mM propylthiouracil. 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 femtomoles of T4 per minute per milligram of protein.
Mitochondrial UCP-1 levels were measured by Western blot after 5 µg total mitochondrial protein were resolved in a 12% SDS-PAGE and electrotransferred to a polyvinylidene difluoride membrane (18). Anti-UCP-1 antiserum was a gift from Dr. J. Enrique Silva (Jewish General Hospital, Montréal, Canada) and was used at a 1:2000 dilution.
Statistical analysis
Results are presented as the mean ± SEM. Due to technical complexities of the D2 and UCP-1 analyses, sample sizes differed in some groups, as noted in Table 1
and Fig. 1. It is assumed that the data analyzed represent a random selection of the animals in the study. Although 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 were 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 (version 10.1, SPSS, Inc., Chicago, IL). P < 0.05 was considered statistically significant.
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Results |
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shows the food intake, weight gain, weights of brown and white fat, and D2 activity in BAT. NPY- and Y1 and Y5 receptor agonist-treated animals consumed significantly more food than controls during the 3 d of infusion. The weight gains of NPY- and Y1 and Y5 receptor agonist-treated animals were similar and approximately 200% of the weight gain of controls. Pair-fed Y1 and pair-fed Y5 receptor agonist-treated animals gained significantly less weight than controls. The weight of the interscapular BAT of the NPY- and Y1 and Y5 receptor agonist-treated and pair-fed Y1 receptor agonist-treated animals was approximately 300% of the BAT weight of controls. The BAT weight of the pair-fed Y5 receptor agonist-treated animals was intermediate. The characteristic deep reddish-brown color of this tissue changed to a light tan or white color in all experimental groups, including the pair-fed groups. The weight of the epididymal fat pad, however, did not increase in either the Y1 or pair-fed Y1 receptor agonist groups, but increased significantly in the NPY and Y5 and pair-fed Y5 receptor agonist groups. Nevertheless, increased fat accumulation was observed in the mediastinum of all experimental and pair-fed groups. D2 activity in brown adipose tissue was significantly increased in the NPY and Y1 and Y5 receptor agonist-treated animals compared with controls, particularly in the Y5 receptor agonist-treated group. Animals receiving the Y1 receptor agonist but pair-fed to controls, however, had D2 activity levels that were intermediate between those of ad libitum feeding, Y1 receptor agonist-treated animals and controls and statistically indistinguishable from those in either group. In addition, animals in the pair-fed Y5 receptor agonist group had significantly lower D2 levels than the Y5 receptor agonist group eating ad libitum, but significantly greater than the control group. The UCP-1 mitochondrial concentration in BAT similarly increased significantly in the Y1 and Y5 receptor agonist-treated groups and was significantly different compared with that in aCSF-treated controls (Fig. 1). Y1 and Y5 receptor agonist-treated animals pair-fed to controls had UCP-1 levels significantly different from those in their respective Y1 and Y5 receptor agonist-treated groups and intermediate between control and experimental values.
Effects of central NPY and Y1 and Y5 receptor agonist administration on serum hormone levels
Serum hormone levels are shown in Table 2. Serum T4 and T3 levels were significantly reduced in all experimental and pair-fed groups compared with control values, particularly in the Y1 and pair-fed Y1 receptor agonist groups, in which T4 and T3 levels were significantly lower than in the Y5 agonist group. TSH was decreased or inappropriately normal for the reduction in thyroid hormone levels in all experimental groups, but again was lowest in the NPY and Y1 and pair-fed Y1 receptor agonist groups.
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Effects of NPY and Y1 and Y5 receptor agonist 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). NPY and Y1 and Y5 receptor agonist administration caused a marked reduction in the hybridization signal over paraventricular proTRH neurons (Fig. 2, B, C, and E). Similar inhibition of proTRH mRNA synthesis was also observed in the pair-fed Y1 and pair-fed Y5 receptor agonist-treated animals (Fig. 2, D and F). By image analysis, the sum of integrated density values of proTRH mRNA in the PVN was significantly decreased to approximately 50–80% of the control (aCSF) value in the NPY- and Y1 and Y5 receptor agonist-treated groups (Fig. 3). There were no significant differences between the integrated density values of the fed and pair-fed Y1 and Y5 receptor agonist groups or between the integrated density values of the NPY- and Y1 and Y5 receptor agonist-treated groups.
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Discussion |
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Although NPY and the Y5 receptor agonist significantly increased epididymal white fat, administration of the Y1 receptor agonist had no significant effect. Nevertheless, NPY and the Y1 and Y5 receptor agonists similarly increased fat accumulation in interscapular BAT and mediastinal white adipose tissue and resulted in similar elevations in circulating leptin levels. Whether this observation indicates that unique NPY receptors regulate fat accumulation in discrete anatomical regions in response to the central effects of NPY will require further study. Interestingly, the animals receiving Y1 or Y5 receptor agonists but pair-fed to controls lost a significant amount of weight compared with controls despite a similar amount of food intake and the suggestion of increased lipogenesis, as evident by the light color of the BAT and the increased leptin levels. Explanations for the weight loss include the effect of centrally administered NPY to induce diuresis (21) or the possibility that the well recognized effect of NPY to increase the level of circulating corticosterone (22) decreased lean body mass as a result of increased proteolysis (23).
Similar to NPY, both Y1 and Y5 receptor agonists markedly reduced the synthesis of proTRH mRNA in the periventricular and medial parvocellular subdivisions of the PVN, reducing TRH mRNA levels to less than 50% of control values. However, this inhibitory action of the Y1 and Y5 receptor agonists prevailed only in hypophysiotropic TRH neurons and was without apparent effect on proTRH gene expression in the lateral hypothalamus. Animals receiving either the Y1 or Y5 receptor agonist but pair-fed to controls also had reduced proTRH mRNA levels in the PVN that were not significantly different from those in the Y1 or Y5 receptor agonist-treated ad libitum feeding groups. Although the absolute value of proTRH mRNA in the Y1 receptor agonist-treated group was lower than that in the Y5 receptor agonist-treated group, the values were not significantly different (P > 0.05, by Newman-Keuls test). Nevertheless, whereas both Y1 and Y5 receptor agonists reduced thyroid hormone levels (T3 and T4) compared with the control group, the reduction in the Y1 receptor agonist group was particularly pronounced and significantly lower than that in the Y5 receptor agonist group, and in the case of circulating T3 levels was significantly lower than NPY itself. Although this may simply reflect a dose effect, the Y5 receptor agonist is approximately twice as potent as NPY (13), whereas the Y1 receptor agonist is nearly equivalent to NPY (12), raising the possibility that NPY may have a particularly potent effect at Y1 receptors to inhibit the thyroid axis.
TSH levels in the NPY and Y1 and Y5 receptor agonist groups were inappropriately low for the circulating thyroid hormone levels and consistent with central hypothyroidism (24). Pair-feeding of Y1 and Y5 receptor agonist-treated animals with controls did not change the effects of the selective agonists on TSH or any other parameter related to the thyroid axis, indicating that both Y1 and Y5 receptor agonists influenced the HPT axis independently of weight gain and increased food intake. Therefore, as both Y1 and Y5 receptor agonist administration could reproduce the profound inhibitory effects of NPY on the HPT axis, we suggest that both Y1 and Y5 receptors play similar roles in the regulation of the HPT axis, primarily by creating a state of central hypothyroidism. Although the Y2 receptor does not appear to be involved in the NPY-induced feeding response (25), the fact that Y2 receptor mRNA is expressed in the parvocellular parts of the PVN (26) raises the possibility that Y2 receptors could also contribute to the inhibitory effect of NPY on the thyroid axis.
Activation of both Y1 and Y5 receptors are mediated through a common intracellular pathway, as both receptor subtypes decrease intracellular levels of cAMP in vitro (8). The cAMP signaling pathway has an important role in the regulation of the proTRH gene, as evident by the presence of a multifunctional cAMP response element in the TRH promoter that is activated by the phosphorylated form of cAMP response element-binding protein (CREB) (27, 28, 29). Furthermore, the cAMP-CREB signaling system in hypophysiotropic TRH neurons is involved in the activation of the proTRH gene by 
MSH (29, 30) and can be attenuated by coadministration of NPY (31), supporting a functional interaction between NPY and MSH in the regulation of proTRH via the cAMP-CREB signaling system.
In addition to central effects of NPY and the NPY receptor agonists on thyroid function through direct actions on TRH gene expression in hypophysiotropic neurons and in concert with our previous observations using NPY (1), both Y1 and Y5 receptor agonists increased D2 activity in BAT, the most important homeostatic T3-producing deiodinase (32). Although we had originally attributed the rise in D2 to the fall in T4 induced by NPY (33), BAT D2 activity was significantly greater in the Y5 receptor agonist-treated animals than in the Y1 receptor agonist-treated animals despite lower thyroid hormone levels in the latter group. In addition, in both the Y1 and Y5 receptor agonist pair-fed groups, D2 activity in BAT was significantly lower than that in ad libitum-fed groups. These data raise the possibility that the increase in D2 activity in BAT associated with the administration of NPY may not be mediated primarily by the fall in thyroid hormone levels, but, rather, that other mechanisms secondary to the increased food consumption and/or weight gain are involved. Along these lines, it is noteworthy that circulating levels of leptin were substantially reduced in the pair-fed group receiving the Y5 receptor agonist, suggesting that leptin may be an important factor that contributes to the regulation of D2 activity in BAT.
UCP-1 levels were also measured in BAT as an index of the biological activity of NPY and the NPY receptor antagonists, but contrary to what might have been expected given the weight gain and fat accumulation in these animals, UCP-1 levels were also elevated. The dissociation between UCP-1 levels and thermogenesis has been recognized in other animal models, including GC-1-treated hypothyroid mice, a thyroid hormone receptor ß-selective agonist (34), and animals with targeted disruption of the Dio2 gene (18). We have also observed this phenomenon in ad libitum-fed animals receiving NPY or AGRP icv, in which elevated UCP-1 levels coincide with increased lipogenesis and triglyceride accumulation in brown adipocytes (35). We presume that the ability of the NPY agonists to inhibit sympathetic outflow to BAT, and hence the release of norepinephrine, prevents lipolysis-induced UCP-1. As the level of UCP-1 in BAT was significantly lower in pair-fed animals receiving the NPY receptor agonists compared with ad libitum-fed animals, however, the effect on UCP-1 is probably mediated by indirect effects, perhaps circulating levels of leptin.
We conclude that administration of the highly selective Y1 and Y5 receptor agonists closely replicates the effects of NPY on the regulation of food intake and the HPT axis. The ability of each agonist to independently suppress proTRH mRNA in the PVN and circulating thyroid hormone levels indicates that either receptor can mediate the inhibitory effects of NPY on the thyroid axis.
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Acknowledgments |
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Footnotes |
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Abbreviations: aCSF, Artificial cerebrospinal fluid; Aib, aminoisobutyric acid; BAT, brown adipose tissue; cPP, chicken pancreatic polypeptide; CREB, cAMP response element-binding protein; CSF, cerebrospinal fluid; hPP, human pancreatic polypeptide; HPT axis, hypothalamic-pituitary-thyroid axis; icv, intracerebroventricular; NPY, neuropeptide Y; PP, pancreatic polypeptide; PVN, paraventricular nucleus; UCP-1, uncoupling protein-1.
Received June 3, 2002.
Accepted for publication August 5, 2002.
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References |
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-melanocyte stimulating hormone increases phosphorylation of CREB in TRH- and CRH-producing neurons of the hypothalamic paraventricular nucleus. Brain Res 945:50–59[CrossRef][Medline]
-MSH-induced CREB phosphorylation in proTRH neurons and increases CREB phosphorylation in CRH neurons in the hypothalamic paraventricular nucleus (PVN). Endocrinology, in press
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