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Tupper Research Institute and Department of Medicine (G.L., R.M.L.), Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine, New England Medical Center, Boston, Massachusetts 02111; 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, Diabetes, Metabolism and Molecular Medicine, Box 268, New England Medical Center, 750 Washington Street, Boston, Massachusetts 02111.
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-MSH, at MC1 receptors in the
skin to reduce pigmentation and MC4 receptors in the brain to inhibit
the hypophagic action of -MSH (1, 2). Targeted deletion of the MC4
receptor gene causes an obesity syndrome similar to the Ay/a
mouse but without the defect in pigmentation, further implicating a
specific role of central MC4 receptors in the regulation of food intake
(3). Subsequently, agouti-related protein (AGRP), a homolog of the
agouti protein, was identified as an endogenous MC4 receptor antagonist
(4, 5). In addition, AGRP overexpression in transgenic mice results in
a phenotype identical to the MC4 knock-out mice (6). AGRP messenger RNA (mRNA) has been identified in neurons of the hypothalamic arcuate nucleus, where it coexists with the mRNA for the potent orexigenic peptide, neuropeptide Y (NPY) (7, 8). Both transcripts are simultaneously up-regulated during fasting and, in the leptin-deficient ob/ob mouse, paralleled by a reduction in POMC expression within a separate group of arcuate neurons (7, 9, 10). Previous studies from our laboratory and others demonstrated that nerve terminals containing NPY-immunoreactivity (-ir) densely innervate TRH neurons in the paraventricular nucleus (PVN) (11, 12, 13), originating almost exclusively from arcuate nucleus neurons (12). In addition, AGRP-immunoreactive nerve fibers have recently been described in the parvocellular areas of the PVN (8, 14). Therefore, we hypothesized that AGRP nerve terminals would innervate hypophysiotropic TRH neurons. In this study, we performed a series of double-labeling immunohistochemical studies, at the light and electron microscopic levels, to determine whether AGRP-containing terminals establish synaptic relationships with TRH neurons and whether this innervation is derived from the arcuate nucleus.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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One group of rats received stereotaxically placed injections of colchicine (low dose, 30–75 µg; high dose, 200 µg) into the lateral cerebral ventricle (icv) under sodium pentobarbital anesthesia. After a survival period of 12–18 h (low dose) or 2 days (high dose), colchicine-treated rats (n = 9), as well as untreated rats (n = 4), were deeply anesthetized; and their brains were perfused via the ascending aorta briefly with heparinized saline, followed by a mixture of 3.75% acrolein and 2% paraformaldehyde in 0.1 M phosphate buffer (PB) for 10–20 min. After perfusion, the brains were removed, postfixed by immersion in 2% paraformaldehyde for 1–2 h, and stored in 0.01 M PBS, pH 7.4, until prepared for immunohistochemistry. From both colchicine-treated and untreated rats, blocks of the hypothalamus were sectioned coronally at 30 µm on a Vibratome (Technical Products International, Inc., St. Louis, MO) and collected into vials containing PBS.
In a second group (n = 6), animals were treated neonatally with monosodium glutamate (MSG) to pharmacologically ablate the arcuate nucleus (15, 16). MSG was administered sc, at the dose of 2 mg/g BW, on postnatal days 2 and 4, followed by 4 mg/g BW on days 6, 8, and 10, while control littermates received saline vehicle only (16). Animals were allowed to survive until the age of 2–3 months and were treated with 75 µg colchicine icv and perfused as described above. Thirty-micrometer-thick hypothalamic sections were stored in a cryoprotectant solution (20% glycerol and 30% ethylene glycol in 0.05 M PB) at -20 C until they were prepared for immunolabeling. Adequacy of the MSG lesion was determined in adult animals by light microscopic examination of cresyl violet-stained coronal sections through the caudal hypothalamus and compared with age-matched control animals (n = 6), as was reported previously (12).
Single labeling immunohistochemistry
Sections were treated with 1% sodium borohydride for 30 min
(dissolved in distilled water for light microscopy or in 0.05
M PB for electron microscopy) followed by 0.5% hydrogen
peroxide in PBS for 15 min. Sections intended for light microscopy were
washed in PBS containing 0.5% Triton X-100 for 1–4 h, and sections
intended for electron microscopy were rinsed in PBS only. After
preincubation in 10% normal horse serum for 1 h, sections were
placed in a rabbit antiserum against AGRP (Phoenix Pharmaceuticals, Inc., Mountain View, CA) at 1:4,000–8,000 for
light microscopy and at 1:6,000 for electron microscopy. Antiserum was
diluted in PBS containing 1% normal horse serum, 0.008% sodium azide,
and 0.2% Kodak Photo-Flo and was incubated with the sections for 3
days, at 4 C, under continuous gentle agitation on a rotary shaker. The
sections were washed in PBS three times and incubated in biotinylated
antirabbit IgG (1:200, Vector Laboratories, Inc.,
Burlingame, CA) for 3 h at room temperature. After three washes in
PBS, the sections were incubated in avidin-biotin-peroxidase complex
(ABC Elite, 1:100, Vector Laboratories, Inc.) for 1 h
and rinsed in 0.05 M Tris buffer, and immunolabeling was
visualized with a mixture of 0.025% diaminobenzidine (DAB) and
0.0036% hydrogen peroxide for 7–12 min. Development was terminated by
extensive washing in 0.05 M Tris buffer. Sections for light
microscopy were mounted onto gelatin-coated slides, air-dried,
dehydrated, and coverslipped. Sections for electron microscopy,
containing the PVN, were further processed for double immunolabeling
(see below).
Specificity of immunolabeling was established by preabsorption of the working dilution of the antiserum with the peptide antigen [AGRP (83–132)-NH2; Phoenix Pharmaceuticals, Inc.] at 10 µM.
Double-labeling immunohistochemistry
To visualize possible neuroanatomical associations of AGRP-ir
nerve terminals and TRH-ir neurons in the PVN, a double-labeling
immunoperoxidase method, using distinct chromogens for the two
peptides, was performed. First, AGRP-fibers were visualized with DAB in
PVN sections, as described above; then, the sections were incubated in
a well-characterized TRH antiserum (17) at 1:24,000–40,000 for 2–3
days at 4 C and were developed using benzidine dihydrochloride (BDHC),
which yields a final product distinguishable from DAB (18). The BDHC
product in TRH-immunopositive perikarya and dendrites appears granular,
dark blue-green before osmication, or granular gray, after osmication
in flat-embedded sections (see below), when examined light
microscopically. After incubation in the anti-TRH antiserum, sections
were washed in PBS and sequentially incubated in biotinylated
antirabbit IgG (1:400 for 1 h), followed by
avidin-biotin-peroxidase complex for 1 h at room temperature. The
sections were washed in PBS, followed by a rinse in 0.05 M
PB (pH 6.5), and placed in 0.01% BDHC and 0.025% sodium nitroprusside
in 0.01 M PB (pH 6.5) for 1 min, which was replaced by a
fresh BDHC solution containing 0.0048% hydrogen peroxide for 2 min.
Development was rapidly terminated by a rinse in 0.05 M PB
at pH 6.5. Free-floating sections were treated with 1% osmium
tetroxide in 0.05 M PB (at pH 6.5) for 20–30 min and
dehydrated in an ascending series of ethanol, followed by propylene
oxide. Sections were infiltrated with epoxy resin (Durcupan ACM,
Fluka Chemical Co., Ronkonkoma, NY) and flat-embedded onto
liquid release agent (Electron Microscopy Sciences, Fort Washington,
PA)-coated slides, and the resin was polymerized for 3 days at 56 C.
Double-labeled, flat-embedded PVN sections were photographed at the
light microscopic level, then the PVN was cut out with a microscalpel,
affixed onto resin blocks with cyanoacrylate glue, and sectioned on an
MRC MT6000 (MRC, Inc., Tucson, AZ) ultramicrotome. Series of ultrathin
sections with silver-gold interference color were collected onto
Formvar-coated single-slot grids and were examined, without heavy metal
contrasting, in a Philips CM-10 transmission electron microscope. As an
alternative approach to improve preservation of ultrastructural
details, a procedure of silver-intensified immunogold reaction for TRH
immunoreactivity was also used for electron microscopy, adapted from
previous publications (19, 20). Briefly, PVN sections, containing the
AGRP immunolabeling product developed by DAB, were incubated in the
rabbit TRH antiserum at 1:10,000 overnight at 4 C, followed by three
washes in PBS and incubation in 0.5% BSA and 0.1% gelatin in PBS, to
reduce nonspecific accumulation of colloidal gold to the surface of the
sections. This was followed by a 3-h incubation in antirabbit IgG
conjugated to 0.8 nm colloidal gold (Electron Microscopy Sciences)
diluted at 1:100 in PBS containing 0.1% cold-water fish skin gelatin.
The sections were rinsed in the same diluent for 5–10 min, further
washed in PBS, and treated in 1.25% glutaraldehyde in PBS for 10 min.
The sections were rinsed in PBS, followed by 0.2 M sodium
citrate at pH 7.5. Silver intensification of the gold particles was
performed using IntenSE Kit (Amersham Pharmacia Biotech,
Arlington Heights, IL) for 6–8 min. The intensification reaction was
terminated by a rinse in 0.2 M sodium citrate, followed by
0.1 M PB. Sections were treated with 2% osmium tetroxide
in 0.1 M PB (at pH 7.4) for 1 h, and dehydrated, and
embedded in Durcupan, and ultrathin sections were prepared as described
above.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The arcuate nucleus was abundant in AGRP-ir containing neuronal
elements; both cell bodies and processes (Fig. 1
). Occasionally, AGRP-immunopositive
cell bodies were also found in the internal zone of the median eminence
(Fig. 1B). Bipolar AGRP neurons with dendrites extended along the
ventricle were located medially; whereas, in the lateral aspects of the
arcuate nucleus, larger multipolar perikarya were observed (Fig. 1B).
The overall diameter of the cell bodies varied between approximately
12–18 µm. In addition to the arcuate and dorsomedial nuclei, dorsal
hypothalamic and retrochiasmatic areas contained medium- to high
densities of AGRP-immunolabeled axonal processes and terminals (Figs. 1A and 2B). Occasionally (only in animals
treated with the high colchicine dose), isolated, lightly labeled
AGRP-ir containing perikarya (not more than 1–2 per section) also
appeared at the ventrolateral border of the caudal dorsomedial nucleus
(data not shown).
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). In the anterior parvocellular subdivision,
moderate densities of nerve fibers and terminals were observed (Fig. 2A), and the density of labeled fibers gradually increased toward the
more caudal levels of the PVN. The parvocellular dorsal cap contained
medium- to high densities of AGRP-labeled fibers; and high densities of
AGRP-positive fibers were also observed in the ventral parvocellular
subdivision, whereas the magnocellular division contained only low
densities (Fig. 2B). In the caudal one-third of the PVN, high densities
of nerve terminals were observed in the medial and periventricular
parvocellular subdivisions (Fig. 2C). At this level, a band of
AGRP-immunolabeled fibers, coursing through the lateral posterior
parvocellular subdivision toward the medial parvocellular subdivision,
was seen, which seemed to be contiguous with a medium density fiber
network in the dorsalmost part of the medial forebrain bundle/lateral
hypothalamic area (Fig. 2, D and E).
The effect of MSG-induced arcuate nucleus ablation on AGRP-ir in
the hypothalamus
Neonatal MSG treatment caused an extensive degenerative lesion in
the arcuate nucleus, which resulted in the nearly complete
disappearance of AGRP-ir-positive neurons and nerve fibers from the
arcuate nucleus at all rostrocaudal levels (Fig. 3, A and B). In addition, nerve fibers
and terminals containing AGRP-ir were virtually absent from the PVN and
all regions of the hypothalamus, with only rare scattered fibers
remaining (Fig. 3, C and D).
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). TRH neurons in
this area were often inundated by AGRP nerve terminals, closely apposed
to their perikarya and first-order dendrites (Fig. 4, B, C, and D). In
sharp contrast to the PVN, an adjacent group of TRH neurons in the
perifornical area did not receive innervation by AGRP-fibers (Fig. 4A).
In the anterior parvocellular subdivision of the PVN, AGRP-ir
containing axons with beaded terminals encircled TRH cell bodies and
followed their first-order dendrites, literally outlining the surface
of TRH neurons (Fig. 5, A and B). TRH
neurons in ventral parvocellular subdivision and the parvocellular
dorsal cap were likewise contacted by AGRP nerve terminals (Fig. 5, C
and D).
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). TRH-immunopositive cell bodies and
dendrites were recognized by the presence of crystalline BDHC or, as
illustrated in Figs. 6 and 7, by the
highly-electron-dense deposits of immunogold-silver particles
distributed throughout the labeled structures. Close membrane
appositions between TRH perikarya and dendrites and AGRP terminals were
commonly observed. In some instances, as many as 4–6 AGRP-labeled
terminals contacted a single TRH cell body and its first-order
dendrites within the same ultrathin section (Fig. 6). Examination of
serial ultrathin sections at higher magnification showed that the
majority of these contacts made synaptic specializations (Fig. 7).
Analysis of 57 consecutive axosomatic and axodendritic synapses,
between AGRP nerve terminals and TRH neurons in the medial
parvocellular and periventricular subdivisions of the PVN from three
separate animals, revealed that 88% were symmetric, 7% were
asymmetric, and in the remaining 5% of the synapses the synaptic
density could not be unequivocally classified.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have recently demonstrated that falling plasma levels of leptin, an anorectic hormone secreted by adipose tissue, act as a critical signal to hypophysiotropic TRH neurons to reset their sensitivity to inhibitory feedback effects of thyroid hormone; when fasting animals were administered leptin exogenously, proTRH gene expression in the PVN and plasma total and free thyroid hormone levels could be restored to normal (26). We have hypothesized that the effects of leptin on hypophysiotropic TRH neurons are not exerted directly but, rather, via neural projections from the hypothalamic arcuate nucleus to the PVN. This assumption is based on the relative paucity of leptin receptor mRNA in the PVN, whereas arcuate nucleus neurons abundantly express leptin receptor mRNA (27), and that ablation of the arcuate nucleus prevents the ability of leptin to restore the HPT axis to normal in fasting animals (28).
One of the mediators that may modulate the effects of leptin on the thyroid axis is the potent orexigenic peptide, NPY (29). NPY-containing axon terminals establish numerous synaptic contacts with TRH neurons in the PVN (11, 13), which originate primarily from the arcuate nucleus (12). During fasting, NPY gene expression dramatically increases in the arcuate nucleus with the concomitant rise in radioimmunoassayable NPY concentrations in the PVN, but not in other regions of the brain (30). Conversely, NPY gene expression in the arcuate nucleus is suppressed by leptin administration (31). Because central NPY may be inhibitory to the thyroid axis (32), we have suggested that this peptide may contribute to the resetting of the HPT axis during fasting (26). Nevertheless, mice with targeted deletion of the NPY gene retain the ability to suppress thyroid hormone levels with fasting (33), suggesting that mechanisms other than the activation of the NPYergic arcuate-PVN pathway are also important for this homeostatic response. In the present study, we demonstrate that AGRP nerve terminals heavily innervate practically all TRH neurons within the PVN, highly reminiscent of that observed for NPY, both at the light- and electron microscopic levels. TRH perikarya and their proximal dendrites were often contacted by AGRP-nerve terminals establishing primarily symmetric synaptic contacts. In contrast, TRH neurons adjacent to the PVN in the perifornical region were not contacted by AGRP-fibers, indicating selectivity of the AGRP input, specifically to TRH neurons in the PVN.
The presence of symmetric synapses by NPY fibers onto perikarya and proximal dendrites of parvocellular PVN neurons, including those immunolabeled for TRH, seems to be characteristic of the NPY input originating from the arcuate nucleus, and this suggests an inhibitory action (13, 34). Because the overwhelming majority of NPY neurons of the rodent arcuate nucleus coexpress AGRP (7, 8), it is likely that the same neurons in the arcuate nucleus give rise to both the NPY- and AGRP innervation of hypophysiotropic TRH neurons. As ablation of the arcuate nucleus abolished AGRP immunolabeling in the PVN, we surmise that the origin of the AGRP innervation to TRH neurons in the PVN originates exclusively from the arcuate nucleus, confirming recent observations by Broberger et al. (8) in the mouse. Because AGRP gene expression increases with fasting and can be inhibited by leptin (7, 10), the potential for this peptide to contribute to the modulation of the thyroid axis during fasting seems to be strong.
Although AGRP innervation of TRH neurons in the medial and periventricular parvocellular subdivisions suggests the potential importance of this peptide in the regulation of hypophysiotropic neurons, TRH neurons in the anterior, dorsal and ventral parvocellular subdivisions were also innervated by AGRP nerve terminals. These latter TRH neurons are not believed to have direct hypophysiotropic function as they do not project to the median eminence (23, 35). Since many neurons in the dorsal and ventral parvocellular subdivisions send projections to parasympathetic and sympathetic centers in the brain stem and spinal cord (36), AGRP may be involved in autonomic regulation. During fasting, therefore, when AGRP gene expression is elevated, AGRP may simultaneously influence hypophysiotropic neurons, as well as the autonomic nervous system, through its input to TRH neurons in the PVN.
AGRP is thought to exert its main effects by binding to melanocortin
receptors and antagonizing the actions of POMC-derived peptides such as
-MSH (37). Therefore, the presence of a major AGRP-innervation of
TRH neurons in the PVN could imply that TRH neurons might also be
modulated by -MSH. Potential contacts between axons containing
POMC-derived peptides and TRH perikarya in the PVN have been reported
at the light microscopic level (38) and confirmed by recent studies in
our laboratory using a specific antiserum to -MSH (Fekete et
al., unpublished data), raising the possibility of converging AGRP
and -MSH input to the same TRH neurons. Concerning the thyroid axis,
-MSH has been reported to increase the uptake of 131I in
the thyroid gland (39), but little is known about its mechanisms of
action, particularly on TRH neurons. Ablation of the arcuate nucleus by
neonatal MSG treatment, which nearly abolishes NPY (12, 16, 40) and
AGRP-neurons (8), is not associated with an increase in basal thyroid
hormone levels or proTRH gene expression in the PVN of adult animals
but, rather, a modest decline in proTRH mRNA in the face of
significantly suppressed thyroid hormone levels (28). This finding
allowed us to hypothesize that the intact arcuate nucleus may exert a
net stimulatory influence on hypophysiotropic TRH neurons (28). As
-MSH is synthesized by arcuate nucleus neurons (41) and would also
be largely abolished by the MSG lesions (42), the potential role of
-MSH in contributing to a tonic stimulatory effect of the arcuate
nucleus on the HPT axis requires further investigation.
In addition to binding to the melanocortin receptor, AGRP may
also have independent mechanisms of action. The C-terminal,
biologically active region of the AGRP molecule contains several
disulfide bonds and shares structural similarities with 
-agatoxin
IVB, a spider venom toxin with P-type Ca2+-channel blocking
properties (43). If AGRP can indeed function as a
Ca2+-channel blocker, it may inhibit
Ca2+-currents postsynaptically, analogous to the effects of
the inhibitory neurotransmitter, GABA acting on the GABAB
receptor (44). Support for melanocortin receptor-independent actions
for AGRP may also be based on the finding that, in the adrenal medulla,
where AGRP mRNA is highly expressed, no matching localization of MC4 or
MC3 receptors was found (4).
Nevertheless, in addition to the PVN, AGRP-ir has also been found in
other regions of the hypothalamus that clearly match the distribution
of the localization of -MSH fibers and MC4 receptors (8, 14, 41, 45). The existence of common local targets for the two ligands in such
regions as the PVN, arcuate and dorsomedial nuclei, lateral
hypothalamus, and preoptic area (8), which collectively are important
sites for the control of food intake and thermoregulatory functions
(21, 46), suggests that AGRP and -MSH may integrate a number of
hypothalamic responses during fasting.
In summary, we demonstrate a widespread (but discrete) distribution of nerve terminals with AGRP-ir in the rat hypothalamus, originating exclusively from the arcuate nucleus. High levels of immunolabeled nerve fibers were observed in areas that are associated with the regulation of feeding behavior, such as the PVN, dorsomedial nucleus, and arcuate nucleus. Because we detected a particularly robust innervation of TRH neurons in the PVN, a morphological substrate for the down-regulation of TRH gene expression during fasting may include AGRP in the arcuato-paraventricular neuronal pathway.
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Acknowledgments |
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Footnotes |
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Received January 4, 1999.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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- and ß-melanocyte stimulating hormones and other peptides on the
thyroid in mice. Endocrinology 74:559–566
- MSH on fever and normal temperature control in
rabbits. Brain Res Bull 18:473–477[CrossRef][Medline]
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C. S. Mantzoros, M. Ozata, A. B. Negrao, M. A. Suchard, M. Ziotopoulou, S. Caglayan, R. M. Elashoff, R. J. Cogswell, P. Negro, V. Liberty, et al. Synchronicity of Frequently Sampled Thyrotropin (TSH) and Leptin Concentrations in Healthy Adults and Leptin-Deficient Subjects: Evidence for Possible Partial TSH Regulation by Leptin in Humans J. Clin. Endocrinol. Metab., July 1, 2001; 86(7): 3284 - 3291. [Abstract] [Full Text] [PDF]
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Y. Takatsu, H. Matsumoto, T. Ohtaki, S. Kumano, C. Kitada, H. Onda, O. Nishimura, and M. Fujino Distribution of Galanin-Like Peptide in the Rat Brain Endocrinology, April 1, 2001; 142(4): 1626 - 1634. [Abstract] [Full Text]
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C. J. Small, M. S. Kim, S. A. Stanley, J. R.D. Mitchell, K. Murphy, D. G.A. Morgan, M. A. Ghatei, and S. R. Bloom Effects of Chronic Central Nervous System Administration of Agouti-Related Protein in Pair-Fed Animals Diabetes, February 1, 2001; 50(2): 248 - 254. [Abstract] [Full Text]
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C. Fekete, E. Mihaly, L.-G. Luo, J. Kelly, J. T. Clausen, Q. Mao, W. M. Rand, L. G. Moss, M. Kuhar, C. H. Emerson, et al. Association of Cocaine- and Amphetamine-Regulated Transcript-Immunoreactive Elements with Thyrotropin-Releasing Hormone-Synthesizing Neurons in the Hypothalamic Paraventricular Nucleus and Its Role in the Regulation of the Hypothalamic-Pituitary-Thyroid Axis during Fasting J. Neurosci., December 15, 2000; 20(24): 9224 - 9234. [Abstract] [Full Text] [PDF]
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E. Mihály, C. Fekete, J. B. Tatro, Z. Liposits, E. G. Stopa, and R. M. Lechan Hypophysiotropic Thyrotropin-Releasing Hormone-Synthesizing Neurons in the Human Hypothalamus Are Innervated by Neuropeptide Y, Agouti-Related Protein, and {alpha}-Melanocyte-Stimulating Hormone J. Clin. Endocrinol. Metab., July 1, 2000; 85(7): 2596 - 2603. [Abstract] [Full Text]
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C. Fekete, G. Legradi, E. Mihaly, Q.-H. Huang, J. B. Tatro, W. M. Rand, C. H. Emerson, and R. M. Lechan alpha -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., February 15, 2000; 20(4): 1550 - 1558. [Abstract] [Full Text] [PDF]
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 E. A. Nillni, C. Vaslet, M. Harris, A. Hollenberg, C. Bjorbak, and J. S. Flier Leptin Regulates Prothyrotropin-releasing Hormone Biosynthesis. EVIDENCE FOR DIRECT AND INDIRECT PATHWAYS J. Biol. Chem., November 10, 2000; 275(46): 36124 - 36133. [Abstract] [Full Text] [PDF]
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