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Tupper Research Institute and Department of Medicine (C.F., J.K., E.M., S.S., G.L., R.M.L.), Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine, New England Medical Center, Boston, Massachusetts 02111; Department of Neurobiology (C.F.), Institute of Experimental Medicine, Hungarian Academy of Sciences, Budapest, Hungary 1083; Department of Community Health (W.M.R.), Tufts University School of Medicine, Boston, Massachusetts 02111; Department of Medicine (C.H.E.), Division of Endocrinology, University of Massachusetts Medical School, Worcester, Massachusetts 01655; and Department of Neuroscience (R.M.L.), Tufts University School of Medicine, Boston, Massachusetts 02111
Address all correspondence and requests for reprints to: Ronald M. Lechan M.D., Ph.D., Professor of Medicine, Division of Endocrinology, Box No. 268, 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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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have recently demonstrated that leptin has an important central action on the hypothalamic-pituitary-thyroid (HPT) axis (3). Thus, with fasting, the reduction in circulating thyroid hormone levels and pro-TRH gene expression in the hypothalamic paraventricular nucleus (PVN) can be completely restored to normal, fed levels by the systemic administration of leptin, despite continuation of the fast (3). We have proposed, therefore, that the fall in circulating leptin levels during fasting resets the set point for feedback inhibition of thyroid hormone on the biosynthesis of hypophysiotropic proTRH in the hypothalamic PVN (3). On the basis that pharmacological ablation of the hypothalamic arcuate nucleus can obliterate the effects of fasting and exogenous leptin administration to fasting animals on the HPT axis (4), we have further hypothesized that the arcuate nucleus mediates the regulatory effects of leptin on the HPT axis and therefore, that the ability of leptin to affect proTRH gene expression in the PVN is indirect (4).
One peptide of arcuate nucleus origin that may mediate the effects of leptin on hypophysiotropic proTRH neurons is the 36 amino acid neuropeptide Y (NPY). NPY-containing axon terminals of arcuate nucleus origin densely innervate TRH neurons in the PVN (5, 6) and establish primarily symmetric contacts that would suggest an inhibitory effect (7). In addition, TRH neurons in the PVN contain type Y1 NPY receptors (8), suggesting a direct action of NPY on these neurons. NPY neurons in the arcuate nucleus contain leptin receptors (9) and fasting markedly increases NPY gene expression in the arcuate nucleus concomitant with increased NPY release in the PVN (10, 11). Therefore, we have raised the possibility that NPY mediates the inhibitory effects of fasting on proTRH neurons in the PVN. To test this hypothesis, we have determined whether the central administration of NPY to fed animals can replicate the response of the HPT axis observed during fasting.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Animal preparation for NPY infusion
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.
Animals were weighed daily and any animal showing signs of illness or
weight loss was removed from the study and euthanized. One week after
icv cannulation, under general anesthesia, an osmotic minipump (Alzet
Model 2001, Alza Corp., 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. In the first experiment, all animals had free
access to food and the animals were divided in two groups. The osmotic
minipumps delivered either 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, pH7.4)
(Group 1, n = 8), or 10 µg/24 h NPY in a-CSF (Group 2, n =
4) for 4 days at a rate of 1 µl/h. In the second experiment, the
first and second groups were fed ad libitum. The first group
(n = 6) received a-CSF, and the second group (n = 6) received
10 µg/24 h NPY in a-CSF by osmotic minipump as described above for 3
days at a rate of 1 µl/h. The third group (n = 4) was also
treated with 10 µg/24 h NPY in a-CSF for 3 days at a rate of 1
µl/h, but pair fed to the control group. 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 0900–1200 h, blood was taken from inferior vena cava for measurement of plasma T4, T3, TSH, and leptin, and the animals were 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. 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 and the arcuate
nucleus were cut on a cryostat (Reichert-Jung 2800 Frigocut-E) 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 and the arcuate nucleus. 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 1,241-bp
single stranded [35S]UTP labeled complementary
RNA probe for pro-TRH as previously described (12, 13).
Serial sections taken from the arcuate nucleus of the animals from the
first experiment were hybridized with a labeled 345-bp single stranded
antisense, [35S]UTP RNA probe for AGRP,
generously provided by Dr. G. Barsh (Stanford University School of
Medicine, Stanford, CA) and previously characterized by Wilson et
al. (14). The hybridizations were performed under
plastic coverslips in a buffer containing 50% formamide, a 2-fold
concentration of standard sodium citrate (2 x SSC), 10% dextran
sulfate, 0.5% SDS, 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 2 days (proTRH) or 7 days (AGRP) 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
(proTRH) or the arcuate nucleus (AGRP) were measured in five
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
(15). Materials for the TSH RIA were provided by the
NIADDK 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 0.22 ng/ml and the ED50 was
3.6 ng/ml. The Cobra 500 program was used for data reduction and
calculation of the RIA results.
Statistical analysis
The results are presented as mean ± SEM. Data
for experiment one (comparing two groups) were analyzed using
independent sample t tests. Data for experiment two
(comparing three groups) were analyzed using ANOVA with two linear
contrasts to test the two basic hypotheses: the first compared the two
treatment groups (NPY and NPY pair fed) and the second compared the
pooled treatment groups (NPY) with the control data. Levene’s test was
used to check the assumption of equality of variance and this showed
that the leptin data needed a log transform before analysis. All data
were entered into and analyzed using SPSS, Inc. Version
10.0. P values are presented, a level less than 0.05 was
considered statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, body weight and weight gain of the two
groups at the end of the experiment did not significantly differ (body
weight P = 0.98, Percent Weight Gain P
= 0.84). NPY administration, however, resulted in an approximately
270% increase in the weight of interscapular brown adipose tissue
(P < 0.013) and a change in the characteristic deep
reddish-brown color of this tissue to a light tan or white color. The
weight of the epididymal fat pad also increased in the NPY treated
animals, and was significantly different from the control group
(P = 0.019).
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, body weights differed
between the NPY ad lib and pair fed groups at the end of the
experiment (as expected). However, change in body weight did not differ
between the NPY groups (P = 0.30), whereas change in
body weight did differ between the NPY groups and the controls
(P < 0.001). The weights of brown fat and epididymal
fat in animals infused with NPY and pair fed to controls were not
significantly different from animals infused with NPY and allowed to
eat ad lib (P = 0.30 and 0.11,
respectively), whereas the combined NPY groups were significantly
different from the weight of brown fat (P < 0.001) and
epididymal fat (P = 0.011) in the control animals.
Table 1 shows the results of plasma thyroid hormone levels, TSH, and
leptin determinations in both experiments. Significant reductions in
plasma levels of T4 (P < 0.001)
and T3 (P = 0.001) were observed
in the NPY-infused animals in the first experiment. TSH was not
significantly different from controls (P = 0.27) but
was considered inappropriately low for the fall in
T4 and T3. No significant
differences between the T4 (P =
0.60), T3 (P = 0.57) and TSH
(P = 0.15) levels were observed between the NPY-infused
ad lib group and the NPY-infused pair fed group in the
second experiment. In addition, the combined NPY groups in the second
experiment were significantly different from the vehicle-infused
controls (T4, P = 0.004;
T3, P = 0.014; TSH,
P = 0.002). Serum leptin levels were markedly increased
by NPY treatment. The natural logs of the leptin values showed
significant differences from their control values in both experiments
(Exp 1, P < 0.001; Exp 2, NPY vs. Control,
P < 0.001). However, significant differences were
found between the ln leptin levels of the NPY ad lib and NPY
pair fed groups (P = 0.016), with the NPY pair fed
group having an intermediate value between the NPY ad lib
group and Controls.
Effect of NPY administration on proTRH messenger RNA (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. 1A). Following the
administration of NPY, a marked decrease in the hybridization signal
was apparent (Fig. 1B). By image analysis, NPY induced an approximately
55% reduction in the density values of proTRH mRNA in PVN neurons,
which was significantly different from controls (P =
0.018) (Fig. 1C).
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, A and B). The NPY pair fed group
also showed a marked reduction in proTRH mRNA that was not perceptibly
different from that in the NPY-infused ad lib fed group
(Fig. 2C). Image analysis revealed an approximately 60% fall in the
NPY pair fed group and 53% in the NPY ad lib group
(P = 0.67 between these two groups), and a very
significant difference comparing the pooled NPY groups to controls
(P = 0.002, Fig. 3).
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). Following the infusion of NPY,
there was a reduction in the intensity of hybridization signal over
these neurons (Fig. 4B), which by image analysis, was significantly
reduced (P = 0.017) to approximately 49% of the
control animals (Fig. 4C).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The possibility that NPY could exert an inhibitory effect on the thyroid axis was first suggested by Harfstrand et al. (24). Following a single icv injection of NPY, these investigators showed a significant reduction in serum levels of TSH within 60 min of administration that could also be reproduced in NPY-treated anesthetized animals, indicating that the response was not secondary to increased food and water consumption. Harfstrand et al. (24) proposed that the effect of NPY to reduce serum TSH may be secondary to activation of tuberoinfundibular dopamine neurons, because NPY increases dopamine utilization in the median eminence (24) and dopamine may be inhibitory to the release of TRH from the median eminence (25) and TSH from anterior pituitary thyrotropes (26).
The dense NPY-ergic innervation of the PVN, however, raises the possibility that NPY could have direct effects on hypophysiotropic TRH neurons. At least two major sources of the NPY innervation of the PVN have been established, the hypothalamic arcuate nucleus (27, 28) and adrenergic/noradrenergic cell groups in the medulla oblongata (29). Studies from our laboratory have identified that the arcuate nucleus is the major source of the NPY innervation, specifically to TRH neurons in the PVN (6). Following ablation of the arcuate nucleus, an approximately 82% reduction in the relative number of NPY terminals contacting TRH perikarya and first order dendrites was observed. However, no statistically significant change in the number of NPY-terminals in close apposition to hypophysiotropic TRH neurons followed lesions of the ascending adrenergic bundle that carries input from the lower brain stem (6). Similar conclusions have been made by other investigators (30). Because the ultrastructural characteristics of the NPY-containing axon terminals that establish synapses with TRH neurons in the PVN are primarily symmetric (6), and neurophysiological studies indicate that symmetric synapses correlate with inhibitory activity (7), we have hypothesized that NPY exerts an inhibitory effect on the thyroid axis via a direct arcuate-paraventricular projection pathway to hypophysiotropic TRH neurons (6).
In the present study, we demonstrate that NPY exerts a profound inhibitory effect on the thyroid axis via effects on hypophysiotropic TRH neurons. The dose of NPY chosen was based on previous studies that demonstrated an orixogenic response when 10 µg of NPY was administered icv (31). Consistent with these observations was a marked increase in food consumption in the NPY-infused animals compared with the vehicle controls in our studies, as well as an increase in weights of brown and white adipose tissue, confirming the efficacy of the infused NPY dose. The increased weight of brown adipose tissue was most likely due to the accumulation of lipids, considering the light color of the brown adipose tissue in the NPY treated animals, as well as the effects of NPY to decrease sympathetic activity and thermogenesis (18).
Associated with the anticipated effects of NPY infusion on food consumption and fat accumulation, there was a significant fall in T4 and T3 levels in the NPY infused animals in both experiments. Plasma TSH was either significantly low or inappropriately normal for the T4 and T3 levels in these animals, suggesting decreased levels of hypophysiotropic TRH (32). Indeed, TRH mRNA in the PVN was significantly reduced compared with vehicle-infused controls in both experiments, falling to more than 50% of control values. The ability of NPY to suppress TRH gene expression in the PVN was unrelated to its effects on food consumption as TRH mRNA in the PVN of the pair fed NPY-infused group was similarly reduced, and essentially no different than the NPY-infused ad lib fed group. These data are also consistent with recent findings, showing that NPY can reduce TRH biosynthesis in cultures of rat fetal hypothalamus (33). This marked inhibition of TRH gene expression in PVN together with the fall in circulating thyroid hormone levels, resembles the effect of fasting on the thyroid axis due to suppression of circulating leptin levels (3).
The increase in leptin levels in NPY infused animals is consistent with other reports (34) and with the increased fat accumulation in these animals. We have previously demonstrated, however, that in fasting animals, exogenous leptin administration restores the hypothalamic-pituitary-thyroid axis to normal (3). It would seem paradoxical in this study, therefore, that despite high circulating levels of leptin, the thyroid axis was suppressed. Several possibilities should be considered. First, the NPY-infused animals may have become leptin resistant. Leptin resistance has been associated with obesity either due to reduced transport of leptin across the blood-brain-barrier, down-regulation of leptin receptors in the brain, or inhibition of downstream signaling (35, 36, 37). However, in most studies, more than three weeks of overfeeding or 2 weeks of chronic high dose leptin administration is required before leptin resistance takes place (38). In our study, the duration of NPY infusion with the resultant overfeeding was limited to 3–4 days. In addition, AGRP mRNA in arcuate nucleus neurons was reduced in the NPY infused animals, whereas in the leptin resistant mouse (db/db) or rat (fa/fa), AGRP mRNA is markedly increased (39, 40), making leptin resistance less likely in our study. The suppression of AGRP mRNA in NPY-infused animals may be due to the effect of hyperphagia-induced hyperleptinemia, consistent with the inhibitory role of leptin on AGRP gene expression (40), or a direct effect of NPY, itself.
An alternative explanation is that the neuromodulatory effects of leptin on the hypothalamic-pituitary-thyroid axis were completely overcome by the central administration of NPY. We have proposed that leptin exerts its effects on hypophysiotropic TRH neurons primarily via the arcuate nucleus, as the arcuate nucleus contains neurons that possess the long (biologically active) form of the leptin receptor (41) and a proportion of arcuate neurons project directly to TRH-producing neurons in the PVN (6, 42, 43). In addition, pharmacological ablation of the arcuate nucleus abolishes fasting-induced inhibition of the thyroid axis and the ability of leptin to regulate TRH gene expression in paraventricular neurons (4). The increased release of NPY from axon terminals in the PVN during fasting when leptin levels are suppressed (11), therefore, may be responsible for the inhibition of TRH gene expression in hypophysiotropic neurons by direct effects on these neurons and/or by interaction with the inhibitory neurotransmitter, GABA, which coexists with NPY in approximately 30% of arcuate nucleus neurons (44, 45). Conversely, the rise in circulating leptin levels would inhibit both the production of NPY in the arcuate nucleus and its release in the PVN, resulting in disinhibition of TRH gene expression. By administering NPY into the CSF, a unique situation is created whereby NPY can bypass any regulatory effects of leptin on the arcuate nucleus as a result of direct access to TRH neurons in the PVN.
The possibility that leptin might have a direct effect on TRH neurons in the PVN has been suggested by Nillni et al. (33) on the basis that a small population (8–13%) of TRH neurons contain leptin receptors and that leptin can dose dependently stimulate proTRH biosynthesis. These studies, however, were performed in cultures of hypothalamic neurons that contain a mixed population of TRH neurons originating in the lateral hypothalamus, dorsomedial nucleus, and perifornical group, in addition to the PVN. Furthermore, whereas leptin can induce the TRH promoter in CV-1 cells cotransfected with the leptin receptor, STAT3, and the human TRH promoter (33), leptin receptors have not yet been demonstrated in hypophysiotropic TRH neurons. In addition, STAT3 is a common intracellular signaling molecule for many cytokines and hormones and is not specific for leptin (46, 47, 48). Finally, because we found that the icv administration of NPY to fed animals inhibits TRH gene expression in PVN neurons, despite high circulating levels of leptin, the effect of leptin on hypophysiotropic TRH, if present, is probably minor. There may be a direct effect of leptin on TRH neurons that do not subserve a hypophysiotropic function, however.
Although the icv administration of NPY was capable of reducing TRH mRNA
in the PVN to levels observed in fasting animals, studies by Erickson
et al. (49), using the NPY knock-out mouse,
have shown that these animals are still capable of suppressing their
thyroid axis during fasting (49). These studies would
suggest that other mechanisms may also be involved in the regulation of
the thyroid axis during fasting and may involve several other peptides
of arcuate nucleus origin including AGRP, 
MSH, and CART (43, 50, 51). Kim et al. (50) have
demonstrated an inhibitory effect of AGRP on TSH secretion in
vivo and on leptin-induced release of TRH from hypothalamic
explants. Conversely, studies from our laboratory have shown that both
-MSH and CART have potent stimulatory effects on TRH gene
expression, selectively in the PVN, and can completely restore proTRH
mRNA levels to normal in fasting animals (43, 51). Thus,
the fasting-induced increase in AGRP and/or decrease in MSH and CART
(40, 52), may contribute to inhibition of the thyroid
axis. In situ hybridization studies for AGRP, POMC, and CART
mRNA have not revealed compensatory changes in the NPY-KO mice
(53). However, target neurons may have altered sensitivity
for AGRP, as NPY-KO animals respond to AGRP administration with a
significantly higher food intake than wild-type animals
(53).
In summary, we conclude that NPY can exert a potent central effect to inhibit TRH gene expression in the PVN. We propose, therefore, that during fasting, activation of NPY-producing neurons in the hypothalamic arcuate nucleus is a major component of the regulatory mechanism that causes a decline in proTRH mRNA in the PVN and in circulating thyroid hormone levels. Because inhibitory effects of icv NPY on the HPT axis occur despite elevated serum leptin concentrations, it is likely that leptin reverses fasting-related declines in the HPT axis by altering NPY expression in the arcuate nucleus and not by direct effects on the PVN.
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Footnotes |
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Received December 27, 2000.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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acid in stimulation of feeding: a morphological and pharmacological
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J. Kallio, U. Pesonen, U. Jaakkola, M. K. Karvonen, H. Helenius, and M. Koulu Changes in Diurnal Sympathoadrenal Balance and Pituitary Hormone Secretion in Subjects with Leu7Pro Polymorphism in the Prepro-Neuropeptide Y J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3278 - 3283. [Abstract] [Full Text] [PDF]
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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]
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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. |
