 |
 Previous Article | Next Article 
The Journal of Neuroscience, February 15, 2000, 20(4):1550-1558
 -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
Csaba
Fekete1, 2,
Gábor
Légrádi1,
Emese
Mihály1,
Qin-Heng
Huang1,
Jeffrey B.
Tatro1,
William M.
Rand3,
Charles H.
Emerson4, and
Ronald M.
Lechan1, 5
1 Tupper Research Institute and Department of Medicine,
Division of Endocrinology, Diabetes, Metabolism, and Molecular
Medicine, New England Medical Center, Boston, Massachusetts 02111, 2 Department of Neurobiology, Institute of Experimental
Medicine, Hungarian Academy of Sciences, Budapest, Hungary,
3 Department of Community Health, Tufts University School
of Medicine, Boston, Massachusetts 02111, 4 Department of
Medicine, Division of Endocrinology, University of Massachusetts
Medical School, Worcester, Massachusetts 01655, and
5 Department of Neuroscience, Tufts University School of
Medicine, Boston, Massachusetts 02111
 |
ABSTRACT |
The hypothalamic arcuate nucleus has an essential role in mediating
the homeostatic responses of the thyroid axis to fasting by altering
the sensitivity of prothyrotropin-releasing hormone (pro-TRH)
gene expression in the paraventricular nucleus (PVN) to feedback
regulation by thyroid hormone. Because agouti-related protein (AGRP), a
leptin-regulated, arcuate nucleus-derived peptide with  -MSH
antagonist activity, is contained in axon terminals that terminate on
TRH neurons in the PVN, we raised the possibility that -MSH may also
participate in the mechanism by which leptin influences pro-TRH gene
expression. By double-labeling immunocytochemistry, -MSH-IR axon
varicosities were juxtaposed to ~70% of pro-TRH neurons in the
anterior and periventricular parvocellular subdivisions of the PVN and
to 34% of pro-TRH neurons in the medial parvocellular subdivision,
establishing synaptic contacts both on the cell soma and dendrites. All
pro-TRH neurons receiving contacts by -MSH-containing fibers also
were innervated by axons containing AGRP. The intracerebroventricular infusion of 300 ng of -MSH every 6 hr for 3 d prevented
fasting-induced suppression of pro-TRH in the PVN but had no effect on
AGRP mRNA in the arcuate nucleus. -MSH also increased circulating
levels of free thyroxine (T4) 2.5-fold over the levels in fasted
controls, but free T4 did not reach the levels in fed controls. These
data suggest that -MSH has an important role in the activation of pro-TRH gene expression in hypophysiotropic neurons via either a mono-
and/or multisynaptic pathway to the PVN, but factors in addition to
-MSH also contribute to the mechanism by which leptin administration
restores thyroid hormone levels to normal in fasted animals.
Key words:
thyrotropin-releasing hormone; thyroid axis; -MSH; arcuate nucleus; fasting; agouti-related protein; leptin
| |
INTRODUCTION |
The biosynthesis and secretion of
thyrotropin-releasing hormone (TRH) in hypophysiotropic neurons of the
paraventricular nucleus (PVN) are regulated by a negative feedback
control mechanism that depends on circulating levels of thyroid hormone
(Koller et al., 1987 ; Segerson et al., 1987; Kakucska et al., 1992).
During fasting, however, when thyroid hormone levels fall, a seemingly
paradoxical reduction in hypophysiotropic TRH and an inappropriately
normal or low plasma thyrotropin (TSH) are observed, consistent with central hypothyroidism (Rondeel et al., 1992; van Haasteren et al.,
1995; Legradi et al., 1997). These alterations can be completely reversed by the systemic administration of leptin to fasting animals (Legradi et al., 1997), leading us to propose that the arcuate nucleus,
a major locus for the central actions of leptin (Hakansson et al.,
1996; Huang et al., 1996; Mercer et al., 1996; Schwartz et al., 1996),
can reset the sensitivity of hypophysiotropic neurons to the feedback
effects of thyroid hormone (Legradi et al., 1998). In support of this
hypothesis, ablation of the arcuate nucleus abolishes the effect of
fasting and leptin administration to fasting animals on pro-TRH gene
expression in the PVN (Legradi et al., 1998). Potential inhibitory
regulators of TRH that mediate the effect of fasting are neuropeptide Y
(NPY) and agouti-related protein (AGRP), both contained within a
monosynaptic pathway originating from arcuate nucleus neurons and
terminating on TRH neurons in the PVN (Legradi and Lechan, 1998, 1999).
Because AGRP is believed to exert its biological activity by
antagonizing melanocortin receptors (Ollmann et al., 1997), its mRNA is
regulated inversely to pro-opiomelanocortin (POMC) mRNA by fasting and
leptin administration (Schwartz et al., 1997; Mizuno et al., 1998;
Mizuno and Mobbs, 1999), and interaction between AGRP and -MSH, the
latter a cleavage product of POMC, is involved in the regulation of
body weight (Fan et al., 1997; Rossi et al., 1998), we questioned
whether -MSH may also be involved in the regulation of the
hypothalamic-pituitary-thyroid axis as a stimulatory factor.
In this study, therefore, we determined whether axons containing
-MSH establish morphological relationships with TRH-producing
neurons in the PVN and whether the intracerebroventricular administration of synthetic -MSH to fasting animals is capable of
restoring pro-TRH mRNA levels in hypophysiotropic neurons toward normal.
| |
MATERIALS AND METHODS |
Animals. The experiments were performed on adult male
Sprague Dawley rats (Taconic, Germantown, NY), weighing 210-230
gm. The animals were housed individually in cages under standard
environmental conditions (light between 0600 and 1800 hr; temperature,
22 ± 1°C; rat chow and water available ad libitum).
All experimental protocols were reviewed and approved by the Animal
Welfare Committee at the New England Medical Center and Tufts
University School of Medicine.
Tissue preparation for immunocytochemistry. Eight animals
were deeply anesthetized with sodium pentobarbital (50 mg/kg of body
weight, i.p.) and stereotaxically injected
intracerebroventricularly with 60 µg of colchicine in 6 µl
of 0.9% saline. After 20 hr of survival, the animals were perfused
transcardially with 20 ml of 0.01 M PBS, pH 7.4, containing 15,000 U/l heparin sulfate, followed sequentially by 100 ml
of 2% paraformaldehyde and 4% acrolein in 0.1 M phosphate
buffer (PB), pH 7.4, and 30 ml of 2% paraformaldehyde in the same
buffer. The brains were rapidly removed and stored in PBS for 24 hr at
4°C. Serial 25-µm-thick coronal sections were cut with a vibratome
and collected in PBS. The sections were treated for 30 min with 1%
sodium borohydride in distilled water for light microscopy or with 1%
sodium borohydride in 0.05 M PB for electron microscopy,
followed by 0.5% H2O2 in PBS for 15 min. Light microscopic sections were permeabilized with
0.5% Triton X-100 in PBS overnight at 4°C. To reduce the nonspecific
antibody binding, the sections for both light and electron microscopy
were treated with 2.5% normal horse serum in PBS for 20 min.
Light microscopic double-labeling immunocytochemistry of
-MSH-IR axons and pro-TRH-IR elements in the PVN. Every third
tissue section through the PVN was incubated for 2 d at 4°C in
sheep anti--MSH antiserum, raised in our laboratory, and used at a titer of 1:150,000, diluted in PBS containing 2.5% normal horse serum,
0.2% Kodak Photo-Flo (Eastman Kodak, Rochester, NY), and 0.2% sodium
azide. Specificity of the immunolabeling with this antiserum has been
reported elsewhere (Elias et al., 1998b). After rinses in PBS, the
sections were incubated in biotinylated donkey anti-sheep IgG for 3 hr
(1:500; Jackson ImmunoResearch, West Grove, PA) followed by the
avidin-biotin-peroxidase complex (ABC Elite; 1:100; Vector
Laboratories, Burlingame, CA) in PBS for 2 hr at room temperature. The
immunoreaction product was developed with 0.05% diaminobenzidine
(DAB), 0.15% nickel ammonium sulfate (Ni), and 0.005%
H2O2 in 0.05 M
Tris buffer, pH. 7.6 (TB), and intensified using a modification of the
Gallyas silver intensification technique to yield a black precipitate
(Liposits et al., 1986), but without thioglycolic acid treatment.
After visualization of -MSH, the sections were incubated for 2 d at 4°C in a rabbit antiserum recognizing prepro-TRH 178-199 (a
gift of Dr. E. Redei, Northwestern University, Chicago, IL) diluted
1:25,000. This antiserum has been characterized by Nillni (2000)
and shown by electrophoretic separation of immunoprecipitated radiolabeled peptides from rat hypothalamic neurons in culture to
recognize a 2.6 kDa peptide characteristic of prepro-TRH 178-199. After washing in PBS, the tissue sections were incubated in donkey anti-rabbit IgG (1:500; Jackson ImmunoResearch) and the ABC Elite complex (1:100). The immunolabeling was visualized by 0.025% DAB and
0.0036% H2O2 in TB, alone,
to yield a brown reaction product. Thus, the black, silver-intensified
Ni-DAB labeled -MSH fibers, and the brown, DAB-labeled pro-TRH-IR
elements could be easily distinguished in the same sections.
Light microscopic triple-labeling immunofluorescence of -MSH-
and AGRP-IR fibers and pro-TRH-IR elements in the PVN. To
determine whether pro-TRH-producing neurons in the PVN receive dual
innervation by axon terminals containing -MSH and AGRP, we
visualized the three antigens with three distinct fluorochromes by
fluorescence immunocytochemistry. In the first step, after the
pretreatment described above, tissue sections containing the PVN were
incubated in a mixture of sheep anti--MSH (1:7500) and rabbit
anti-AGRP (1:3000; Phoenix Pharmaceuticals, Mountain View, CA) for
4 d at 4°C. The sections were rinsed in PBS and then incubated
in a mixture of Texas Red-conjugated donkey anti-sheep IgG (1:50;
Jackson ImmunoResearch) and biotinylated donkey anti-rabbit IgG (1:200)
for 2 d at 4°C, followed by further washes and incubation in
avidin-FITC DCS (1:250; Vector Laboratories) for 2 d at
4°C. The tissues were then incubated in rabbit anti-prepro-TRH
178-199 (1:5000) for 4 d at 4°C, followed by incubation in
7-amino-4-methylcoumarin-3-acetic acid (AMCA)-conjugated donkey
anti-rabbit IgG (1:50; Jackson ImmunoResearch) for 2 d at 4°C.
The sections were mounted on gelatin-coated slides, coverslipped with
Vectashield mounting medium (Vector Laboratories), and analyzed under a
Zeiss Axioskop 2 epifluorescent microscope using the following filter
sets: for Texas Red, excitation of 540-590 nm, bandpass of 595 nm, and
emission of 600-660 nm; for FITC, excitation of 460-500 nm, bandpass
of 505 nm, and emission of 510-560 nm; and for AMCA, excitation of
320-400 nm, bandpass of 400 nm, and emission of 430-490 nm. Thus,
-MSH-containing fibers were labeled in red, AGRP-containing fibers
were labeled in green, and pro-TRH-containing perikarya were labeled in
blue under their respective filter sets. Images were captured with a
Spot digital camera (Diagnostic Instrument, Sterling Heights, MI), the
same field triple exposed while switching the filter sets for each
fluorochrome and superimposed using Adobe Photoshop 5.0 and a Macintosh
G3 computer to create a composite image for analysis. Because AGRP-IR
was labeled with FITC before the incubation with antiserum to pro-TRH,
the FITC fluorochrome labeled only the AGRP-IR fibers and not the
TRH-IR elements. Although AMCA-conjugated anti-rabbit IgG labeled both
AGRP- and pro-TRH-IR elements, no AGRP-containing neurons are present
in the PVN (Broberger et al., 1998; Legradi and Lechan, 1999). The
superimposition of the yellow-green fluorescence of FITC and the blue
fluorescence of AMCA in the composite images yielded a green color of
the AGRP-IR fibers, which was distinct from the blue fluorescence
contained in the pro-TRH-IR elements.
Double-labeling electron microscopic immunohistochemistry for
-MSH and pro-TRH in the PVN. Sections processed for electron microscopy were incubated in sheep anti--MSH antiserum (1:20,000) for 4 d at 4°C, followed by biotinylated donkey anti-sheep IgG (1:500) for 12 hr at 4°C and the ABC Elite complex (1:100).
Immunoreactivity was detected with DAB as described above. The sections
were then placed into rabbit anti-prepro-TRH 178-199 (1:8000) for
2 d at 4°C and, after rinsing in PBS and 0.1% cold-water fish
gelatin (Electron Microscopy Sciences, Fort Washington, PA) in PBS,
were incubated in goat anti-rabbit IgG conjugated with 0.8 nm colloidal gold (Electron Microscopy Sciences) diluted at 1:100 in PBS containing 0.1% cold-water fish gelatin. The sections were washed in the same
diluent and PBS, followed by a 10 min treatment in 1.25% glutaraldehyde in PBS. After rinsing in 0.2 M sodium
citrate, pH 7.5, the gold particles were silver intensified with the
IntenSE Kit (Amersham, Arlington Heights, IL) (Branchereau et al.,
1995). Sections were treated with 2% osmium tetroxide in 0.1 M PB for 1 hr, dehydrated in an ascending series of ethanol
followed by propylene oxide, flat embedded in Durcupan ACM epoxy
resin (Fluka, Neu-Ulm, Germany) on liquid release agent
(Electron Microscopy Sciences)-coated slides, and polymerized at
56°C for 2 d. Ultrathin sections were cut with an MRC MT6000
ultramicrotome (MRC, Tuscon, AZ), collected onto Formvar-coated
single-slot grids, and examined without heavy metal contrasting using a
Phillips CM-10 electron microscope.
Animal preparation for -MSH infusion. To determine
whether -MSH is capable of restoring pro-TRH mRNA levels to normal
in fasting animals, we implanted adult Sprague Dawley rats with a 22 gauge stainless steel guide cannula (Plastics One, Roanoke, VA) into
the lateral cerebral ventricle under stereotaxic control (coordinates
from bregma, anteroposterior,  0.8; lateral, 1.2; and 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
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 killed. One week after
intracerebroventricular cannulation, the animals were divided into four
groups. The first group (n = 9) had food available
ad libitum and was injected intracerebroventricularly with 6 µl of artificial CSF (140 mM NaCl, 3.35 mM KCl, 1.15 mM MgCl2, 1.26 mM
CaCl2, 1.2 mM
Na2HPO4, and 0.3 mM
NaH2PO4, pH 7.4) containing 0.1% bovine serum albumin (BSA) every 6 hr for the duration
of the experiment. The second (n = 9), third
(n = 4), and fourth (n = 8) groups were
fasted for 64 hr beginning at 1600 hr on the first day and ending
between 0900 and 1200 hr on the fourth day and injected
intracerebroventricularly with 6 µl of artificial CSF, 150 ng of
-MSH (Peninsula Laboratories, Belmont, CA) in 6 µl of artificial
CSF, or 300 ng of -MSH in 6 µl of artificial CSF, respectively,
every 6 hr. All intracerebroventricular injections were made in freely
moving animals through a 28 gauge needle that extended 1 mm below the
guide cannula, connected by polyethylene tubing to a 50 µl
Hamilton syringe, and was infused over 5 min by an infusion pump (Bee
Electronic Minipump; BAS, West Lafayette, IN). At completion of the
experiment, the animals were anesthetized with sodium pentobarbital,
blood was taken from the inferior vena cava for measurement of serum
thyroxine (T4), free T4, and TSH, and the animals were immediately
perfused with fixative as described below. Blood was collected into
polypropylene tubes and centrifuged for 15 min at 4000 rpm, and the
plasma was stored at 80°C until assayed.
Tissue preparation for in situ hybridization
histochemistry. Under sodium pentobarbital anesthesia, the animals
were perfused transcardially with 20 ml of 0.01 M PBS, pH
7.4, containing 15,000 U/l heparin sulfate, followed by 150 ml of 4%
paraformaldehyde in PBS. The brains were removed and post-fixed by
immersion in the same fixative for 2 hr at room temperature. Tissue
blocks containing the hypothalamus were cryoprotected in 20% sucrose in PBS at 4°C overnight and 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, Houston, TX) to obtain four sets of slides, each set containing every fourth section through the PVN and arcuate nucleus (ARC). Cannula placement was confirmed by light microscopic
examination, and animals with cannulas outside the lateral ventricle
were excluded from further study. 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 base pair single-stranded 35S-UTP-labeled cRNA probe for pro-TRH as
described previously (Dyess et al., 1988; Kakucska et al., 1992).
Serial sections taken from the arcuate nucleus were hybridized with a
labeled 260 base pair 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 Ollmann et al.
(1997). The hybridization was performed under plastic coverslips in a
buffer containing 50% formamide, a twofold concentration of SSC (2×
SSC), 10% dextran sulfate, 0.5% SDS, 250 µg/ml denatured
salmon sperm DNA, and 6 × 105 cpm of
radiolabeled probe for 16 hr at 56°C. Slides were dipped into Kodak
NTB2 autoradiography emulsion (Eastman Kodak), and the
autoradiograms were developed after 2 d (pro-TRH) or 7 d
(AGRP) of exposure at 4°C. The specificity of hybridization was
confirmed using sense probes that resulted in the absence of specific
hybridization in the PVN and arcuate nucleus.
Image analysis. Autoradiograms were visualized at 78× under
dark-field illumination using a COHU 4910 video camera (COHU, San
Diego, CA). The intensity of the light source was maintained constant
by conversion of AC current through a DC power supply (EPSCO, Addison,
IL). The images were captured with a color PCI frame grabber
board (Scion Corporation, Frederick, MD) and analyzed with a Macintosh
G3 computer using Scion Image. Background density points were removed
by thresholding the image, and integrated density values (density × area) of hybridized neurons in the same region of each side of the
PVN or ARC were measured in six consecutive sections for each animal.
Nonlinearity of the 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 2% gelatin fixed with 4% formaldehyde
and exposed and developed simultaneously with the in situ
hybridization autoradiograms.
Hormone measurements. Plasma T4 and TSH concentrations were
measured by RIA. Materials for the TSH RIA were provided by the National Hormone and Pituitary Program (Baltimore, MD) using the National Institute of Diabetes and Digestive and Kidney Diseases rat
TSH RP-2 as the standard. Plasma T4 levels were measured with a
specific RIA using antiserum from Ventrex (Portland, ME) and 125I-labeled T4 obtained from New England
Nuclear (Boston, MA). Equilibrium dialysis was used to determine the
fraction of T4 in plasma that was free. The details of the assay have
been reported previously (Castro et al., 1986). The Cobra 500 program
was used for data reduction and calculation of the RIA results.
Statistical analysis. The results are presented as mean ± SEM. Statistical significance was determined by nested ANOVA,
followed by the Student-Newman-Keuls multiple comparison test.
Differences were considered to be significant at p < 0.05. All statistical analyses were run using SPSS (SPSS, Chicago, IL).
| |
RESULTS |
-MSH-IR innervation of pro-TRH-containing neurons in
the PVN
-MSH-IR axons heavily innervated all major parvocellular
portions of the PVN, but most intensely the anterior, ventral, and periventricular parvocellular subdivisions and the most caudal portion
of the medial parvocellular subdivision (Fig.
1A-C). By double-labeling light microscopic immunocytochemistry, varicose -MSH-IR fibers were in juxtaposition to the majority of pro-TRH-IR neurons in the anterior and periventricular parvocellular subdivisions of the PVN (Fig. 1D,E), whereas substantially fewer
pro-TRH-IR neurons in the medial and dorsal parvocellular subdivision
appeared to be contacted by -MSH axon varicosities (Fig.
1F,G). Cell counts from three animals showed that
~70% of the pro-TRH-containing neurons were found in contact with
-MSH axon varicosities in the anterior (70 ± 3.6%) and
periventricular (72 ± 1.2%) parvocellular subdivisions of the
PVN, whereas <50% of the pro-TRH-containing neurons received contacts
in the medial (34 ± 0.5%) and dorsal (47 ± 0.3%)
parvocellular subdivisions.
View larger version (142K):
[in this window]
[in a new window]
|
Figure 1.
A-C, Low-power photomicrographs
showing the distribution of -MSH-IR axons (black) and
pro-TRH-containing neurons (brown) in different levels
of the PVN. A, Anterior level of the PVN.
B, Mid level of the PVN. C, Caudal level
of the PVN. D-G, High-power magnification of -MSH-IR
axon varicosities (arrows) contacting pro-TRH neurons in
the anterior (D), periventricular
(E), medial (F), and dorsal
(G) parvocellular subdivisions of the PVN. Note
that the majority of the pro-TRH-IR neurons are contacted by -MSH-IR
fibers in the anterior and periventricular subdivisions, whereas fewer
pro-TRH-IR neurons in the medial and dorsal parvocellular subdivisions
appear to be innervated by -MSH-IR axons. H, I,
Triple-labeling fluorescent immunocytochemistry showing dual
innervation of periventricular (a) and medial
(b) parvocellular proTRH neurons
(blue) of the PVN by axon terminals containing -MSH
(red; arrowheads) and AGRP
(green; arrows). Note that
all pro-TRH-containing neurons establishing contacts with -MSH-IR
terminals are also contacted by several AGRP-IR varicosities, whereas
other pro-TRH-IR neurons (asterisks) receive only an
AGRP-IR innervation. AP, Anterior parvocellular
subdivision; DP, dorsal parvocellular subdivision;
MP, medial parvocellular subdivision; PV,
periventricular parvocellular subdivision; VP, ventral
parvocellular subdivision. Scale bars: A-C, 100 µm;
D-I, 20 µm.
|
|
By ultrastructural analysis of the periventricular parvocellular
subdivision, DAB-labeled -MSH-IR terminals containing numerous small
clear vesicles and some dense core vesicles were seen to establish
synapses on pro-TRH neurons, the latter identified by the presence of
the highly electron-dense silver particles (Fig. 2). Tracing the juxtaposed -MSH-IR
terminals and pro-TRH-IR neurons through a series of ultrathin sections
on the same neuron, we observed both axodendritic (Fig.
2A) and axosomatic (Fig. 2B) synaptic specializations.
View larger version (118K):
[in this window]
[in a new window]
|
Figure 2.
Electron micrographs showing synaptic associations
(arrows) between pro-TRH-containing neurons in the PVN
and -MSH-containing axon terminals. The pro-TRH-IR dendrites and
perikarya are labeled with highly electron-dense silver granules,
whereas the -MSH-IR terminals are recognized by the presence of the
electron-dense DAB. A, Medium-power magnification view
of an axodendritic synapse, shown in greater detail in the
inset. B, High-power magnification of an
axosomatic synapse. Scale bars: A, 1 µm; B,
inset, 0.4 µm.
|
|
Dual innervation of pro-TRH-IR neurons by -MSH- and AGRP-IR
terminals in the PVN
By triple-labeling immunofluorescence, AGRP-IR axon varicosities
were found to be juxtaposed to all pro-TRH neurons receiving -MSH-IR
innervation (Fig. 1H,I). The majority of the
double-innervated neurons were found in the anterior and
periventricular subdivisions of the PVN. -MSH- and AGRP-containing
axon varicosities established contacts with both the perikarya and
dendrites of these neurons, but the number of AGRP terminals around
pro-TRH neurons was more numerous than the number of -MSH terminals.
Several pro-TRH-IR neurons were also observed in contact with AGRP
axons, alone (Fig. 1H,I).
Effect of fasting and -MSH administration to fasting animals
on the body weight and plasma hormone levels
Fasted animals lost ~22% of their body weight during the
experiment, whereas the fed controls gained 5% of their body weight. Fasted animals receiving an -MSH intracerebroventricular infusion also showed significant weight reduction (20%), which was not significantly different from the weight loss of the fasted control animals.
Table 1 shows the results of plasma total
and free thyroid hormone and TSH determinations. Serum T4 and free T4
levels were significantly reduced in fasted animals to ~20% of that
in fed controls, whereas the free T4 fraction was significantly
increased and TSH was inappropriately low for the concentration of
thyroid hormone. Administration of 300 ng of -MSH
intracerebroventricularly every 6 hr significantly attenuated the
effect of fasting on thyroid hormone levels and resulted in an
~2.5-fold increase of T4 and free T4 compared with that in fasted
animals and 38 and 52% of fed T4 and free T4 levels, respectively, but
had no effect on the free T4 fraction. TSH values rose in the fasted
animals receiving 300 ng of -MSH, but the values were not
significantly different from that of fed and fasted animals. Infusion
of the lower dose of -MSH (150 ng) to fasted animals had no effects
on any of the measured parameters compared with values in fasted
control animals.
View this table:
[in this window]
[in a new window]
|
Table 1.
Thyroid hormone levels in fed, fasted animals and fasted
animals receiving an intracerebroventricular infusion of -MSH at the
designated dose every 6 hr for 64 hr
|
|
Effect of fasting and -MSH administration in fasting animals on
pro-TRH mRNA in the PVN
In fed animals, neurons containing pro-TRH mRNA were readily
visualized by in situ hybridization histochemistry to be
distributed symmetrically in the medial and periventricular
parvocellular subdivisions of the PVN on either side of the third
ventricle (Fig. 3A), whereas
fasting caused a marked decrease in the hybridization signal over the
paraventricular pro-TRH neurons (Fig. 3B). By image
analysis, the sum of integrated density values of pro-TRH mRNA in the
PVN of fasting animals was 44% of that of the fed animals (see
Fig. 5A). In fasted animals receiving 300 ng of -MSH every 6 hr, however, the hybridization pattern appeared identical to
that of the fed controls (Fig. 3D), and the integrated
density values were not significantly different from the fed levels
(see Fig. 5A). No effect on the hybridization signal was
induced by the lower dose of -MSH when compared with fasted animals
receiving vehicle alone (see Figs. 3C, 5A).
View larger version (122K):
[in this window]
[in a new window]
|
Figure 3.
Dark-field illumination micrographs of pro-TRH
mRNA in the medial and periventricular parvocellular subdivisions of
the hypothalamic PVN in fed (A) and fasted
(B) animals and fasted animals receiving an
intracerebroventricular infusion of -MSH at a dose of 150 ng
(C) or 300 ng (D) every 6 hr for 64 hr. Note the reduction in the accumulation of silver grains
over the PVN in fasted animals compared with the fed controls. Fasted
animals receiving 150 ng of -MSH every 6 hr show suppression of
pro-TRH mRNA in the PVN similar to that of fasted animals receiving
artificial CSF. Fasted animals receiving 300 ng of -MSH every 6 hr,
however, show a marked increase in pro-TRH mRNA that is similar to that
of fed control animals. III, Third ventricle. Scale bar, 100 µm.
|
|
Effect of fasting and -MSH administration in fasting animals on
AGRP mRNA in the arcuate nucleus
In fed animals, neurons containing AGRP mRNA were weakly
visualized by in situ hybridization histochemistry in the
arcuate nucleus (Fig.
4A). In contrast,
silver grains densely accumulated over the AGRP neurons in fasted
animals (Fig. 4B), were distributed in both medial
and lateral portions of the arcuate nucleus, and increased by 740%
compared with fed animals. Neither dose of -MSH to fasted animals
significantly altered the integrated density values for AGRP mRNA
compared with the fasted animals receiving vehicle, alone (Figs.
4C,D, 5B).
View larger version (159K):
[in this window]
[in a new window]
|
Figure 4.
Dark-field illumination micrographs of AGRP mRNA
in the arcuate nucleus of fed (A) and fasted
(B) animals and fasted animals receiving an
intracerebroventricular infusion of -MSH at a dose of 150 ng
(C) or 300 ng (D). Note the
marked increase in AGRP mRNA in the fasted animals. No significant
alteration in AGRP mRNA levels is apparent after -MSH administration
in any of the groups. III, Third ventricle. Scale bar, 100 µm.
|
|
View larger version (12K):
[in this window]
[in a new window]
|
Figure 5.
Computerized image analysis of pro-TRH mRNA
content in the PVN (A) and AGRP mRNA content in
the arcuate nucleus (B) of fed and fasted animals
and fasted animals receiving an intracerebroventricular infusion of
-MSH at a dose of 150 or 300 ng (**p < 0.01 compared with fed animals).
|
|
| |
DISCUSSION |
These studies indicate that -MSH may have an important
physiological role in the regulation of TRH-synthesizing neurons in the
PVN. The presence of a dense network of -MSH-containing axons in the
PVN that establish synaptic contacts both on the soma and first-order
dendrites of pro-TRH-IR neurons provides an anatomical basis to propose
a direct action of -MSH on these neurons. These data are consistent
with previous light microscopic findings that ACTH, also a
post-translational cleavage product of POMC, is contained in axons
adjacent to TRH neurons in the PVN (Liao et al., 1991). Although
-MSH is synthesized in two regions within the brain, the arcuate
nucleus and the nucleus tractus solitarius (Dube et al., 1978; Joseph
et al., 1983), the arcuate nucleus is probably the only source of
-MSH-containing fibers in the PVN. Deafferentation of the mediobasal
hypothalamus that separates the arcuate nucleus from the rest of the
brain results in marked depletion of -MSH in the dorsal hypothalamus
(Eskay et al., 1979), whereas nearly half of the POMC-synthesizing
neurons in the arcuate nucleus are labeled by the retrograde transport
of marker substances injected into the PVN (Sawchenko et al., 1982).
Moreover, the POMC-containing fibers originating from the nucleus
tractus solitarius are fine in appearance and lack varicosities,
characteristically different from the tortuous fibers with numerous
varicosities originating from the arcuate nucleus perikarya (Joseph and
Michael, 1988) and observed to contact pro-TRH neurons. Thus, axons
containing -MSH, like axons containing NPY and AGRP, may contribute
to the arcuato-paraventricular pathway to innervate TRH neurons.
By double-labeling immunocytochemistry, pro-TRH neurons in the anterior
and periventricular parvocellular subdivision of the PVN were observed
to receive dual innervation by both -MSH and AGRP. The potential
importance of this observation is implicit in the knowledge that both
peptides bind melanocortin type 4 receptors (MC4-R) (Adan et al., 1994;
Ollmann et al., 1997), which are expressed in parvocellular neurons in
the PVN (Mountjoy et al., 1994), but have opposing actions. In cell
lines that stably express the MC4-R, AGRP has a potent inhibitory
action, blocking the generation of cAMP stimulated by -MSH (Ollmann
et al., 1997). Similarly, in vivo, intracerebroventricular
administration of -MSH substantially reduces food intake (Rossi et
al., 1998), whereas AGRP increases feeding, blocks the -MSH-induced
reduction of food intake (Rossi et al., 1998), and, when overexpressed
in transgenic mice, causes obesity (Ollmann et al., 1997). Therefore,
the presence of -MSH- and AGRP-containing axons converging on the
same pro-TRH neurons in the PVN provides morphological evidence to
suggest an interaction between melanocortin agonist and antagonistic
effects, respectively, to regulate the transcription of pro-TRH mRNA.
Although all pro-TRH neurons in the PVN that received contacts by
-MSH-containing axon terminals also received contacts by axons
containing AGRP, the majority of pro-TRH neurons in the medial
parvocellular subdivision of the PVN, where most of the hypophysiotropic TRH neurons reside (Ishikawa et al., 1988), were contacted by AGRP- but not -MSH-containing axon terminals. These observations raise the possibilities that AGRP may have actions on
pro-TRH neurons independent of its antagonism of -MSH, either directly on the melanocortin receptor itself or through a separate receptor (Graham et al., 1997; Bures et al., 1998), and that only a
subpopulation of hypophysiotropic pro-TRH neurons in the PVN is under
direct control by -MSH. Nevertheless, whereas fasted animals
receiving only vehicle intracerebroventricularly showed a significant
reduction in pro-TRH mRNA in the PVN compared with fed controls, as
reported previously (Blake et al., 1991; Legradi et al., 1997), the
administration of 300 ng of -MSH intracerebroventricularly every 6 hr completely reversed the effect of fasting on pro-TRH gene
expression, resulting in a hybridization pattern that was identical to
that of the fed animals in all parvocellular subdivisions of the PVN.
No selectivity for increased pro-TRH mRNA in periventricular parvocellular neurons was apparent. Similar observations have been
reported by our group after the systemic administration of recombinant
leptin to fasting animals (Legradi et al., 1997), suggesting that the
increase in endogenous -MSH associated with leptin-induced
activation of POMC gene expression (Schwartz et al., 1997; Mizuno et
al., 1998) may mediate the leptin-induced increase in pro-TRH mRNA in
the PVN.
The anatomical selectivity of -MSH-containing axon terminals for
pro-TRH neurons in the periventricular parvocellular subdivision of the
PVN and the generalized effect of -MSH to increase pro-TRH gene
expression in hypophysiotropic pro-TRH neurons, including medial
parvocellular neurons, raise the possibility that -MSH may exert
both direct and indirect effects on parvocellular neurons in the PVN.
Along these lines, the hypothalamic dorsomedial nucleus (DMN) has well
established projections to the parvocellular PVN (Ter Horst and Luiten,
1987; Thompson et al., 1996) and contains a subpopulation of neurons
that are activated by the systemic administration of leptin (Elmquist
et al., 1998). In addition, the DMN is one of the main targets for both
-MSH- and AGRP-IR fibers (Jacobowitz and O'Donohue, 1978; Broberger
et al., 1998), the latter originating exclusively from the arcuate
nucleus (Broberger et al., 1998; Legradi and Lechan, 1999). Thus, the
possibility of a leptin-responsive, multisynaptic pathway, composed of
-MSH- and AGRP-producing neurons originating in the arcuate nucleus and influencing the activity of the PVN via afferents to the DMN, requires further study. Preliminary observations in our laboratory indicate that regions of the DMN send projections to the medial and
periventricular parvocellular subdivisions of the PVN where they
contact pro-TRH neurons (E. Mihály, C. Fekete, G. Légrádi, R. M. Lechan, unpublished observations).
In contrast to the 300 ng dose of -MSH, the lower 150 ng dose did
not affect pro-TRH mRNA in the PVN, which showed levels similar to that
of the fasting controls. AGRP mRNA, however, was markedly increased by
fasting, rising 8.4-fold over values in fed animals and not suppressed
by either dose of -MSH. This differs from the effects of leptin to
increase POMC gene expression (Schwartz et al., 1997; Mizuno et al.,
1998) simultaneously with marked suppression of AGRP and NPY gene
expression (Schwartz et al., 1996; Mizuno and Mobbs, 1999) when
administered to fasting animals. Thus, in our studies, a certain
threshold level of infused -MSH may have been required in the fasted
animals to antagonize the inhibitory effects of the persistently
elevated endogenous AGRP at the melanocortin receptor, before the
stimulatory effects of exogenous -MSH on the TRH neurons in the PVN
could be realized. In addition, the persistent elevation of AGRP mRNA
in the -MSH-infused animals indicates that the effect of exogenous
-MSH to increase pro-TRH mRNA in the PVN is not caused by inhibition
of AGRP gene expression and that the fall in AGRP mRNA after leptin
administration (Mizuno and Mobbs, 1999) is not mediated by a rise in
-MSH. A negative short-feedback control system involving the
regulation of AGRP gene expression by -MSH, therefore, probably does
not occur in the arcuate nucleus.
Although the higher dose of -MSH was effective in completely
restoring pro-TRH mRNA to fed levels in PVN neurons of fasting animals,
plasma levels of thyroid hormone showed only a partial response, rising
to ~50% of fed levels. The rise in free T4 was greater than that
observed for T4 because of the elevation of the free T4 fraction in all
of the fasting groups, unaffected by -MSH infusion. These data are
consistent with previous observations by our group that reduction in
thyroid hormone-binding proteins in the peripheral circulation by
tasting cannot be restored by leptin and thereby is probably not
centrally mediated (Legradi et al., 1997). TSH did not significantly
change in any of the four groups but was inappropriate for the level of
T4 in fasting animals, suggesting reduction in its biological activity,
likely because of changes in TRH released into the portal system
(Taylor and Weintraub, 1989). Thus, in contrast to the effect of the
systemic administration of leptin to fasting animals, which not only
increases pro-TRH mRNA in the PVN but also fully restores thyroid
hormone levels to normal (Legradi et al., 1997), -MSH appears to
affect only part of the full regulatory effects of leptin on the
thyroid axis, primarily via actions directed on the regulation of
pro-TRH gene expression. Other factors that respond to leptin
administration and act in coordination with -MSH downstream from the
transcription of pro-TRH but are not affected by the
intracerebroventricular administration of -MSH, alone, may also be
necessary to achieve the full regulatory response of leptin on the
thyroid axis. These factors may be peptides whose mRNA is known to be
affected by leptin administration, such as NPY and AGRP in the arcuate
nucleus and orexin and melanin-concentrating hormone in the lateral
hypothalamus that are downregulated by leptin (Schwartz et al., 1996;
Beck and Richy, 1999; Huang et al., 1999) and cocaine- and
amphetamine-regulated transcript that is upregulated by leptin and also
coexpressed in POMC neurons (Elias et al., 1998a; Kristensen et al.,
1998).
We conclude that centrally administered -MSH exerts a potent
stimulatory action on pro-TRH-producing neurons in the PVN, overriding
the inhibitory effects of fasting. This effect may be mediated by a
monosynaptic and/or multisynaptic pathway from the arcuate nucleus to
hypophysiotropic TRH neurons. Thus, -MSH may have an important
central role in the regulation of the thyroid axis and contribute to
the mechanism by which leptin restores thyroid hormone levels to normal
in fasting animals.
| |
FOOTNOTES |
Received Aug. 2, 1999; revised Sept. 27, 1999; accepted Oct. 15, 1999.
This work was supported by National Institutes of Health Grant
DK-37021. We appreciate the expert technical assistance of Marta Powell and Scott Stone.
Correspondence should be addressed to Dr. Ronald M. Lechan, Professor
of Medicine, Division of Endocrinology, Box Number 268, New England
Medical Center, 750 Washington Street, Boston, MA 02111. E-mail
address: rlechan{at}lifespan.org.
| |
REFERENCES |
-
Adan RA,
Cone RD,
Burbach JP,
Gispen WH
(1994)
Differential effects of melanocortin peptides on neural melanocortin receptors.
Mol Pharmacol
46:1182-1190[Abstract].
-
Beck B,
Richy S
(1999)
Hypothalamic hypocretin/orexin and neuropeptide Y: divergent interaction with energy depletion and leptin.
Biochem Biophys Res Commun
258:119-122[Web of Science][Medline].
-
Blake NG,
Eckland DJ,
Foster OJ,
Lightman SL
(1991)
Inhibition of hypothalamic thyrotropin-releasing hormone messenger ribonucleic acid during food deprivation.
Endocrinology
129:2714-2718[Abstract/Free Full Text].
-
Branchereau P,
Van Bockstaele EJ,
Chan J,
Pickel VM
(1995)
Ultrastructural characterization of neurons recorded intracellularly in vivo and injected with lucifer yellow: advantages of immunogold-silver vs. immunoperoxidase labeling.
Microsc Res Tech
30:427-436[Web of Science][Medline].
-
Broberger C,
Johansen J,
Johansson C,
Schalling M,
Hokfelt T
(1998)
The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice.
Proc Natl Acad Sci USA
95:15043-15048[Abstract/Free Full Text].
-
Bures EJ,
Hui JO,
Young Y,
Chow DT,
Katta V,
Rohde MF,
Zeni L,
Rosenfeld RD,
Stark KL,
Haniu M
(1998)
Determination of disulfide structure in agouti-related protein (AGRP) by stepwise reduction and alkylation.
Biochemistry
37:12172-12177[Medline].
-
Castro MI,
Alex S,
Young RA,
Braverman LE,
Emerson CH
(1986)
Total and free serum thyroid hormone concentrations in fetal and adult pregnant and nonpregnant guinea pigs.
Endocrinology
118:533-537[Abstract/Free Full Text].
-
Dube D,
Lissitzky JC,
Leclerc R,
Pelletier G
(1978)
Localization of alpha-melanocyte-stimulating hormone in rat brain and pituitary.
Endocrinology
102:1283-1291[Abstract/Free Full Text].
-
Dyess EM,
Segerson TP,
Liposits Z,
Paull WK,
Kaplan MM,
Wu P,
Jackson IM,
Lechan RM
(1988)
Triiodothyronine exerts direct cell-specific regulation of thyrotropin-releasing hormone gene expression in the hypothalamic paraventricular nucleus.
Endocrinology
123:2291-2297[Abstract/Free Full Text].
-
Elias CF,
Lee C,
Kelly J,
Aschkenasi C,
Ahima RS,
Couceyro PR,
Kuhar MJ,
Saper CB,
Elmquist JK
(1998a)
Leptin activates hypothalamic CART neurons projecting to the spinal cord.
Neuron
21:1375-1385[Web of Science][Medline].
-
Elias CF,
Saper CB,
Maratos-Flier E,
Tritos NA,
Lee C,
Kelly J,
Tatro JB,
Hoffman GE,
Ollmann MM,
Barsh GS,
Sakurai T,
Yanagisawa M,
Elmquist JK
(1998b)
Chemically defined projections linking the mediobasal hypothalamus and the lateral hypothalamic area.
J Comp Neurol
402:442-459[Web of Science][Medline].
-
Elmquist JK,
Ahima RS,
Elias CF,
Flier JS,
Saper CB
(1998)
Leptin activates distinct projections from the dorsomedial and ventromedial hypothalamic nuclei.
Proc Natl Acad Sci USA
95:741-746[Abstract/Free Full Text].
-
Eskay RL,
Giraud P,
Oliver C,
Brown-Stein MJ
(1979)
Distribution of alpha-melanocyte-stimulating hormone in the rat brain: evidence that alpha-MSH-containing cells in the arcuate region send projections to extrahypothalamic areas.
Brain Res
178:55-67[Web of Science][Medline].
-
Fan W,
Boston BA,
Kesterson RA,
Hruby VJ,
Cone RD
(1997)
Role of melanocortinergic neurons in feeding and the agouti obesity syndrome.
Nature
385:165-168[Medline].
-
Graham A,
Wakamatsu K,
Hunt G,
Ito S,
Thody AJ
(1997)
Agouti protein inhibits the production of eumelanin and phaeomelanin in the presence and absence of alpha-melanocyte stimulating hormone.
Pigment Cell Res
10:298-303[Medline].
-
Hakansson ML,
Hulting AL,
Meister B
(1996)
Expression of leptin receptor mRNA in the hypothalamic arcuate nucleus
 relationship with NPY neurones.
NeuroReport
7:3087-3092[Web of Science][Medline]. -
Huang Q,
Viale A,
Picard F,
Nahon J,
Richard D
(1999)
Effects of leptin on melanin-concentrating hormone expression in the brain of lean and obese lepob/lepob mice.
Neuroendocrinology
69:145-153[Web of Science][Medline].
-
Huang XF,
Koutcherov I,
Lin S,
Wang HQ,
Storlien L
(1996)
Localization of leptin receptor mRNA expression in mouse brain.
NeuroReport
7:2635-2638[Web of Science][Medline].
-
Ishikawa K,
Taniguchi Y,
Inoue K,
Kurosumi K,
Suzuki M
(1988)
Immunocytochemical delineation of thyrotrophic area: origin of thyrotropin-releasing hormone in the median eminence.
Neuroendocrinology
47:384-388[Medline].
-
Jacobowitz DM,
O'Donohue TL
(1978)
alpha-Melanocyte stimulating hormone: immunohistochemical identification and mapping in neurons of rat brain.
Proc Natl Acad Sci USA
75:6300-6304[Abstract/Free Full Text].
-
Joseph SA,
Michael GJ
(1988)
Efferent ACTH-IR opiocortin projections from nucleus tractus solitarius: a hypothalamic deafferentation study.
Peptides
9:193-201[Web of Science][Medline].
-
Joseph SA,
Pilcher WH,
Bennett-Clarke C
(1983)
Immunocytochemical localization of ACTH perikarya in nucleus tractus solitarius: evidence for a second opiocortin neuronal system.
Neurosci Lett
38:221-225[Web of Science][Medline].
-
Kakucska I,
Rand W,
Lechan RM
(1992)
Thyrotropin-releasing hormone gene expression in the hypothalamic paraventricular nucleus is dependent upon feedback regulation by both triiodothyronine and thyroxine.
Endocrinology
130:2845-2850[Abstract/Free Full Text].
-
Koller KJ,
Wolff RS,
Warden MK,
Zoeller RT
(1987)
Thyroid hormones regulate levels of thyrotropin-releasing-hormone mRNA in the paraventricular nucleus.
Proc Natl Acad Sci USA
84:7329-7333[Abstract/Free Full Text].
-
Kristensen P,
Judge ME,
Thim L,
Ribel U,
Christjansen KN,
Wulff BS,
Clausen JT,
Jensen PB,
Madsen OD,
Vrang N,
Larsen PJ,
Hastrup S
(1998)
Hypothalamic CART is a new anorectic peptide regulated by leptin.
Nature
393:72-76[Medline].
-
Legradi G,
Lechan RM
(1998)
The arcuate nucleus is the major source for neuropeptide Y-innervation of thyrotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus.
Endocrinology
139:3262-3270[Abstract/Free Full Text].
-
Legradi G,
Lechan RM
(1999)
Agouti-related protein containing nerve terminals innervate thyrotropin-releasing hormone neurons in the hypothalamic paraventricular nucleus.
Endocrinology
140:3643-3652[Abstract/Free Full Text].
-
Legradi G,
Emerson CH,
Ahima RS,
Flier JS,
Lechan RM
(1997)
Leptin prevents fasting-induced suppression of prothyrotropin-releasing hormone messenger ribonucleic acid in neurons of the hypothalamic paraventricular nucleus.
Endocrinology
138:2569-2576[Abstract/Free Full Text].
-
Legradi G,
Emerson CH,
Ahima RS,
Rand WM,
Flier JS,
Lechan RM
(1998)
Arcuate nucleus ablation prevents fasting-induced suppression of ProTRH mRNA in the hypothalamic paraventricular nucleus.
Neuroendocrinology
68:89-97[Web of Science][Medline].
-
Liao N,
Bulant M,
Nicolas P,
Vaudry H,
Pelletier G
(1991)
Anatomical interactions of proopiomelanocortin (POMC)-related peptides, neuropeptide Y (NPY) and dopamine beta-hydroxylase (D beta H) fibers and thyrotropin-releasing hormone (TRH) neurons in the paraventricular nucleus of rat hypothalamus.
Neuropeptides
18:63-67[Medline].
-
Liposits Z,
Sherman D,
Phelix C,
Paull WK
(1986)
A combined light and electron microscopic immunocytochemical method for the simultaneous localization of multiple tissue antigens. Tyrosine hydroxylase immunoreactive innervation of corticotropin releasing factor synthesizing neurons in the paraventricular nucleus of the rat.
Histochemistry
85:95-106[Web of Science][Medline].
-
Mercer JG,
Hoggard N,
Williams LM,
Lawrence CB,
Hannah LT,
Trayhurn P
(1996)
Localization of leptin receptor mRNA and the long form splice variant (Ob-Rb) in mouse hypothalamus and adjacent brain regions by in situ hybridization.
FEBS Lett
387:113-116[Web of Science][Medline].
-
Mizuno TM,
Mobbs CV
(1999)
Hypothalamic agouti-related protein messenger ribonucleic acid is inhibited by leptin and stimulated by fasting.
Endocrinology
140:814-817[Abstract/Free Full Text].
-
Mizuno TM,
Kleopoulos SP,
Bergen HT,
Roberts JL,
Priest CA,
Mobbs CV
(1998)
Hypothalamic pro-opiomelanocortin mRNA is reduced by fasting and in ob/ob and db/db mice, but is stimulated by leptin.
Diabetes
47:294-297[Abstract].
-
Mountjoy KG,
Mortrud MT,
Low MJ,
Simerly RB,
Cone RD
(1994)
Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain.
Mol Endocrinol
8:1298-1308[Abstract/Free Full Text].
-
Nillni EA (2000) Neuroregulation of proTRH biosynthesis and
processing. Endocrinology, in press.
-
Ollmann MM,
Wilson BD,
Yang YK,
Kerns JA,
Chen Y,
Gantz I,
Barsh GS
(1997)
Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein.
Science
278:135-138[Abstract/Free Full Text].
-
Rondeel JM,
Heide R,
de Greef WJ,
van Toor H,
van Haasteren GA,
Klootwijk W,
Visser TJ
(1992)
Effect of starvation and subsequent refeeding on thyroid function and release of hypothalamic thyrotropin-releasing hormone.
Neuroendocrinology
56:348-353[Web of Science][Medline].
-
Rossi M,
Kim MS,
Morgan DG,
Small CJ,
Edwards CM,
Sunter D,
Abusnana S,
Goldstone AP,
Russell SH,
Stanley SA,
Smith DM,
Yagaloff K,
Ghatei MA,
Bloom SR
(1998)
A C-terminal fragment of Agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo.
Endocrinology
139:4428-4431[Abstract/Free Full Text].
-
Sawchenko PE,
Swanson LW,
Joseph SA
(1982)
The distribution and cells of origin of ACTH(1-39)-stained varicosities in the paraventricular and supraoptic nuclei.
Brain Res
232:365-374[Web of Science][Medline].
-
Schwartz MW,
Seeley RJ,
Campfield LA,
Burn P,
Baskin DG
(1996)
Identification of targets of leptin action in rat hypothalamus.
J Clin Invest
98:1101-1106[Web of Science][Medline].
-
Schwartz MW,
Seeley RJ,
Woods SC,
Weigle DS,
Campfield LA,
Burn P,
Baskin DG
(1997)
Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus.
Diabetes
46:2119-2123[Abstract].
-
Segerson TP,
Kauer J,
Wolfe HC,
Mobtaker H,
Wu P,
Jackson IM,
Lechan RM
(1987)
Thyroid hormone regulates TRH biosynthesis in the paraventricular nucleus of the rat hypothalamus.
Science
238:78-80[Abstract/Free Full Text].
-
Taylor T,
Weintraub BD
(1989)
Altered thyrotropin (TSH) carbohydrate structures in hypothalamic hypothyroidism created by paraventricular nuclear lesions are corrected by in vivo TSH-releasing hormone administration.
Endocrinology
125:2198-2203[Abstract/Free Full Text].
-
Ter Horst GJ,
Luiten PG
(1987)
Phaseolus vulgaris leuco-agglutinin tracing of intrahypothalamic connections of the lateral, ventromedial, dorsomedial and paraventricular hypothalamic nuclei in the rat.
Brain Res Bull
18:191-203[Web of Science][Medline].
-
Thompson RH,
Canteras NS,
Swanson LW
(1996)
Organization of projections from the dorsomedial nucleus of the hypothalamus: a PHA-L study in the rat.
J Comp Neurol
376:143-173[Web of Science][Medline].
-
van Haasteren GAC,
Linkels E,
Klootwijk W,
van Toor H,
Rondeel JMM,
Themmen APN,
de Jong FH,
Valentijn K,
Vaudry H,
Bauer K,
Visser TJ,
de Greef WJ
(1995)
Starvation-induced changes in the hypothalamic content of prothyrotrophin-releasing hormone (proTRH) mRNA and the hypothalamic release of proTRH-derived peptides: role of the adrenal gland.
J Endocrinol
145:143-153[Abstract/Free Full Text].
Copyright © 2000 Society for Neuroscience 0270-6474/00/2041550-09$05.00/0
This article has been cited by other articles:
|
|
|
|
 
D. L. Morris and L. Rui
Recent advances in understanding leptin signaling and leptin resistance
Am J Physiol Endocrinol Metab,
December 1, 2009;
297(6):
E1247 - E1259.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. I. Chiamolera and F. E. Wondisford
Thyrotropin-Releasing Hormone and the Thyroid Hormone Feedback Mechanism
Endocrinology,
March 1, 2009;
150(3):
1091 - 1096.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
J. C Garza, C. S. Kim, J. Liu, W. Zhang, and X.-Y. Lu
Adeno-associated virus-mediated knockdown of melanocortin-4 receptor in the paraventricular nucleus of the hypothalamus promotes high-fat diet-induced hyperphagia and obesity
J. Endocrinol.,
June 1, 2008;
197(3):
471 - 482.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
V. Tolle and M. J. Low
In Vivo Evidence for Inverse Agonism of Agouti-Related Peptide in the Central Nervous System of Proopiomelanocortin-Deficient Mice
Diabetes,
January 1, 2008;
57(1):
86 - 94.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. A. Nillni
Regulation of Prohormone Convertases in Hypothalamic Neurons: Implications for ProThyrotropin-Releasing Hormone and Proopiomelanocortin
Endocrinology,
September 1, 2007;
148(9):
4191 - 4200.
[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]
|
|
|
|
|
|
|
M. Lee, A. Kim, S. C. Chua Jr., S. Obici, and S. L. Wardlaw
Transgenic MSH overexpression attenuates the metabolic effects of a high-fat diet
Am J Physiol Endocrinol Metab,
July 1, 2007;
293(1):
E121 - E131.
[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]
|
|
|
|
|
|
|
P. S. Singru, E. Sanchez, C. Fekete, and R. M. Lechan
Importance of Melanocortin Signaling in Refeeding-Induced Neuronal Activation and Satiety
Endocrinology,
February 1, 2007;
148(2):
638 - 646.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Xue, J.-S. Rim, J. C. Hogan, A. A. Coulter, R. A. Koza, and L. P. Kozak
Genetic variability affects the development of brown adipocytes in white fat but not in interscapular brown fat
J. Lipid Res.,
January 1, 2007;
48(1):
41 - 51.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Komatsu, T. Chiba, H. Yamaza, K. To, H. Toyama, Y. Higami, and I. Shimokawa
Effect of leptin on hypothalamic gene expression in calorie-restricted rats.
J. Gerontol. A Biol. Sci. Med. Sci.,
September 1, 2006;
61(9):
890 - 898.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Perello, R. C. Stuart, and E. A. Nillni
The Role of Intracerebroventricular Administration of Leptin in the Stimulation of Prothyrotropin Releasing Hormone Neurons in the Hypothalamic Paraventricular Nucleus
Endocrinology,
July 1, 2006;
147(7):
3296 - 3306.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S.-N. Lee, J. R. Hwang, and I. Lindberg
Neuroendocrine Protein 7B2 Can Be Inactivated by Phosphorylation within the Secretory Pathway
J. Biol. Chem.,
February 10, 2006;
281(6):
3312 - 3320.
[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]
|
|
|
|
|
|
|
B. Xue, A. Coulter, J. S. Rim, R. A. Koza, and L. P. Kozak
Transcriptional Synergy and the Regulation of Ucp1 during Brown Adipocyte Induction in White Fat Depots
Mol. Cell. Biol.,
September 15, 2005;
25(18):
8311 - 8322.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. E. McMinn, S.-M. Liu, H. Liu, I. Dragatsis, P. Dietrich, T. Ludwig, C. N. Boozer, and S. C. Chua Jr.
Neuronal deletion of Lepr elicits diabesity in mice without affecting cold tolerance or fertility
Am J Physiol Endocrinol Metab,
September 1, 2005;
289(3):
E403 - E411.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. W. Kok, F. Roelfsema, S. Overeem, G. J. Lammers, M. Frolich, A. E. Meinders, and H. Pijl
Altered setting of the pituitary-thyroid ensemble in hypocretin-deficient narcoleptic men
Am J Physiol Endocrinol Metab,
May 1, 2005;
288(5):
E892 - E899.
[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]
|
|
|
|
|
|
|
K. Wynne, S. Stanley, B. McGowan, and S. Bloom
Appetite control
J. Endocrinol.,
February 1, 2005;
184(2):
291 - 318.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Guillemin
Hypothalamic hormones a.k.a. hypothalamic releasing factors
J. Endocrinol.,
January 1, 2005;
184(1):
11 - 28.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Hrabovszky, G. Wittmann, G. F. Turi, Z. Liposits, and C. Fekete
Hypophysiotropic Thyrotropin-Releasing Hormone and Corticotropin-Releasing Hormone Neurons of the Rat Contain Vesicular Glutamate Transporter-2
Endocrinology,
January 1, 2005;
146(1):
341 - 347.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. H. Bates, T. A. Dundon, M. Seifert, M. Carlson, E. Maratos-Flier, and M. G. Myers Jr
LRb-STAT3 Signaling Is Required for the Neuroendocrine Regulation of Energy Expenditure by Leptin
Diabetes,
December 1, 2004;
53(12):
3067 - 3073.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Varma, J. He, B.-C. Shin, L. A. Weissfeld, and S. U. Devaskar
Postnatal intracerebroventricular exposure to leptin causes an altered adult female phenotype
Am J Physiol Endocrinol Metab,
December 1, 2004;
287(6):
E1132 - E1141.
[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]
|
|
|
|
|
|
|
J. He, A. Varma, L. A. Weissfeld, and S. U. Devaskar
Postnatal glucocorticoid exposure alters the adult phenotype
Am J Physiol Regulatory Integrative Comp Physiol,
July 1, 2004;
287(1):
R198 - R208.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Huo, H. Munzberg, E. A. Nillni, and C. Bjorbaek
Role of Signal Transducer and Activator of Transcription 3 in Regulation of Hypothalamic trh Gene Expression by Leptin
Endocrinology,
May 1, 2004;
145(5):
2516 - 2523.
[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]
|
|
|
|
|
|
|
C. Fekete, B. Gereben, M. Doleschall, J. W. Harney, J. M. Dora, A. C. Bianco, S. Sarkar, Z. Liposits, W. Rand, C. Emerson, et al.
Lipopolysaccharide Induces Type 2 Iodothyronine Deiodinase in the Mediobasal Hypothalamus: Implications for the Nonthyroidal Illness Syndrome
Endocrinology,
April 1, 2004;
145(4):
1649 - 1655.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. G. Bouret, S. J. Draper, and R. B. Simerly
Formation of Projection Pathways from the Arcuate Nucleus of the Hypothalamus to Hypothalamic Regions Implicated in the Neural Control of Feeding Behavior in Mice
J. Neurosci.,
March 17, 2004;
24(11):
2797 - 2805.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Bjorbaek and B. B. Kahn
Leptin Signaling in the Central Nervous System and the Periphery
Recent Prog. Horm. Res.,
January 1, 2004;
59(1):
305 - 331.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
K. L.J. Ellacott and R. D. Cone
The Central Melanocortin System and the Integration of Short- and Long-term Regulators of Energy Homeostasis
Recent Prog. Horm. Res.,
January 1, 2004;
59(1):
395 - 408.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
A. Randich, P. C. Chandler, H. C. Mebane, M. E. Turnbach, S. T. Meller, G. R. Kelm, and J. E. Cox
Jejunal administration of linoleic acid increases activity of neurons in the paraventricular nucleus of the hypothalamus
Am J Physiol Regulatory Integrative Comp Physiol,
January 1, 2004;
286(1):
R166 - R173.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. L. Williams, R. R. Bowers, T. J. Bartness, J. M. Kaplan, and H. J. Grill
Brainstem Melanocortin 3/4 Receptor Stimulation Increases Uncoupling Protein Gene Expression in Brown Fat
Endocrinology,
November 1, 2003;
144(11):
4692 - 4697.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. F. Turi, Z. Liposits, S. M. Moenter, C. Fekete, and E. Hrabovszky
Origin of Neuropeptide Y-Containing Afferents to Gonadotropin-Releasing Hormone Neurons in Male Mice
Endocrinology,
November 1, 2003;
144(11):
4967 - 4974.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. O'Rahilly, I. S. Farooqi, G. S. H. Yeo, and B. G. Challis
Minireview: Human Obesity--Lessons from Monogenic Disorders
Endocrinology,
September 1, 2003;
144(9):
3757 - 3764.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Liu, T. Kishi, A. G. Roseberry, X. Cai, C. E. Lee, J. M. Montez, J. M. Friedman, and J. K. Elmquist
Transgenic Mice Expressing Green Fluorescent Protein under the Control of the Melanocortin-4 Receptor Promoter
J. Neurosci.,
August 6, 2003;
23(18):
7143 - 7154.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
W. S. Dhillo, C. J. Small, P. H. Jethwa, S. H. Russell, J. V. Gardiner, G. A. Bewick, A. Seth, K. G. Murphy, M. A. Ghatei, and S. R. Bloom
Paraventricular Nucleus Administration of Calcitonin Gene-Related Peptide Inhibits Food Intake and Stimulates the Hypothalamo-Pituitary-Adrenal Axis
Endocrinology,
April 1, 2003;
144(4):
1420 - 1425.
[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. L. Dakin, C. J. Small, A. J. Park, A. Seth, M. A. Ghatei, and S. R. Bloom
Repeated ICV administration of oxyntomodulin causes a greater reduction in body weight gain than in pair-fed rats
Am J Physiol Endocrinol Metab,
December 1, 2002;
283(6):
E1173 - E1177.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Fekete, S. Sarkar, W. M. Rand, J. W. Harney, C. H. Emerson, A. C. Bianco, and R. M. Lechan
Agouti-Related Protein (AGRP) Has a Central Inhibitory Action on the Hypothalamic-Pituitary-Thyroid (HPT) Axis; Comparisons between the Effect of AGRP and Neuropeptide Y on Energy Homeostasis and the HPT Axis
Endocrinology,
October 1, 2002;
143(10):
3846 - 3853.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Hahm, C. Fekete, T. M. Mizuno, J. Windsor, H. Yan, C. N. Boozer, C. Lee, J. K. Elmquist, R. M. Lechan, C. V. Mobbs, et al.
VGF is Required for Obesity Induced by Diet, Gold Thioglucose Treatment, and Agouti and is Differentially Regulated in Pro-Opiomelanocortin- and Neuropeptide Y-Containing Arcuate Neurons in Response to Fasting
J. Neurosci.,
August 15, 2002;
22(16):
6929 - 6938.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Zheng, M. M. Corkern, S. M. Crousillac, L. M. Patterson, C. B. Phifer, and H.-R. Berthoud
Neurochemical phenotype of hypothalamic neurons showing Fos expression 23 h after intracranial AgRP
Am J Physiol Regulatory Integrative Comp Physiol,
June 1, 2002;
282(6):
R1773 - R1781.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Rios, G. Fan, C. Fekete, J. Kelly, B. Bates, R. Kuehn, R. M. Lechan, and R. Jaenisch
Conditional Deletion Of Brain-Derived Neurotrophic Factor in the Postnatal Brain Leads to Obesity and Hyperactivity
Mol. Endocrinol.,
October 1, 2001;
15(10):
1748 - 1757.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. M. Lechan and J. B. Tatro
Editorial: Hypothalamic Melanocortin Signaling in Cachexia
Endocrinology,
August 1, 2001;
142(8):
3288 - 3291.
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. K. Olszewski, M. M. Wirth, T. J. Shaw, M. K. Grace, C. J. Billington, S. Q. Giraudo, and A. S. Levine
Role of {alpha}-MSH in the regulation of consummatory behavior: immunohistochemical evidence
Am J Physiol Regulatory Integrative Comp Physiol,
August 1, 2001;
281(2):
R673 - R680.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
C. Fekete, J. Kelly, E. Mihaly, S. Sarkar, W. M. Rand, G. Legradi, C. H. Emerson, and R. M. Lechan
Neuropeptide Y Has a Central Inhibitory Action on the Hypothalamic-Pituitary-Thyroid Axis
Endocrinology,
June 1, 2001;
142(6):
2606 - 2613.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Makimura, T. M. Mizuno, X.-J. Yang, J. Silverstein, J. Beasley, and C. V. Mobbs
Cerulenin Mimics Effects of Leptin on Metabolic Rate, Food Intake, and Body Weight Independent of the Melanocortin System, but Unlike Leptin, Cerulenin Fails to Block Neuroendocrine Effects of Fasting
Diabetes,
April 1, 2001;
50(4):
733 - 739.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
J. E. McMinn, C. W. Wilkinson, P. J. Havel, S. C. Woods, and M. W. Schwartz
Effect of intracerebroventricular alpha -MSH on food intake, adiposity, c-Fos induction, and neuropeptide expression
Am J Physiol Regulatory Integrative Comp Physiol,
August 1, 2000;
279(2):
R695 - R703.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
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]
|
|
|
|
|
|
|
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]
|
|
|
|
|
TOP
ABSTRACT
INTRODUCTION
