| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
ARTICLES |
Tupper Research Institute and Department of Medicine, Division of Endocrinology, Diabetes, Metabolism and Molecular Medicine, New England Medical Center (G.L., R.M.L.) and Department of Medicine, Division of Endocrinology, Beth Israel-Deaconess Medical Center (R.S.A., J.S.F.), Boston, Massachusetts 02111; University of Massachusetts Medical School (C.H.E.), Worcester, Massachusetts 01655; and Department of Neuroscience (R.M.L.), Tufts University School of Medicine, Boston, Massachusetts 02111
Address all correspondence and requests for reprints to: Ronald M. Lechan, M.D., Ph.D., Professor of Medicine, Division of Endocrinology, Box No. 268, New England Medical Center, 750 Washington Street, Boston, Massachusetts 02111.
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Systemic administration of leptin, an endogenous protein hormone with anorectic activity synthesized and secreted by fat cells (15), blunts the fall in T4 levels during fasting and blunts changes in the adrenal and gonadal axes (16). Because leptin levels are normally suppressed by fasting (17, 18), it was proposed that falling leptin levels provide an important signal that coordinates a number of endocrine responses to starvation, including decreased thyroid thermogenesis, increased stress steroids, and inhibition of reproductive function (16). Because leptin can effect the brain to alter neuropeptide Y mRNA in the arcuate nucleus (19), we hypothesized that the circulating levels of leptin also may be involved in the neuroendocrine regulation of hypophysiotropic proTRH-producing neurons in the PVN during fasting, to explain changes in peripheral thyroid hormone levels. In this study, therefore, we measured the content of proTRH mRNA in the hypothalamus of normally fed and fasted rats and determined whether systemic administration of leptin to fasted rats could have any effect on proTRH biosynthesis in the PVN.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Experimental protocol
Animals were divided into three groups of eight animals each.
The first group was allowed free access to food and water; the second
group was fasted for approximately 65 h, beginning at 1600 h
the first day and ending between 0900 and 1100 h on the last day,
but allowed continued access to drinking water; and the third group was
fasted as above and administered recombinant leptin (Eli Lilly and Co.,
Indianapolis, IN) at a dose of 0.5 µg/gm BW ip every 6 h
beginning two h after the removal of food. All animals were weighed
daily, and at completion of the experiment, they were anesthetized with
pentobarbital (50 mg/kg BW, ip); blood was obtained from the inferior
vena cava for measurement of serum T3,
T4, free T3, free T4, TSH, and
thyroid-binding proteins and immediately perfused with fixative as
described below. Blood was collected into polypropylene tubes,
centrifuged for 15 min at 3500 rpm, and the plasma stored at -80 C
until assayed.
Tissue preparation
After general anesthesia, animals were perfused through the
ascending aorta with 0.01 M PBS, pH 7.2, containing 15,000
U/liter heparin sulfate for 30–60 sec, followed by 4%
paraformaldehyde in PBS for 15 min. Brains were removed, postfixed by
immersion in the same fixative for 6 h, and placed in 20% sucrose
in PBS at 4 C overnight. Serial 18-µm coronal tissue sections through
the rostral-caudal extent of the PVN were obtained on a cryostat
(Reichert-Jung 2800 Frigocut-E) and adhered to Superfrost/Plus glass
slides (Fisher Scientific Co., Pittsburgh, PA) to obtain four sets of
slides (each set containing every fourth tissue section through the
PVN). The tissue sections were desiccated overnight by heating at 42 C
and stored at -80 C until prepared for in situ
hybridization histochemistry.
In situ hybridization histochemistry
Every fourth section taken from the region of the PVN was
hybridized with a single-stranded, [35S]UTP-labeled
complementary RNA probe generated from a 1241-bp
EcoRI-PstI fragment of proTRH complementary DNA
cloned antisense into the plasmid vector pSP65 (Promega Corp., Madison,
WI), as previously described (11, 20). Specificity of hybridized
material in the PVN and lateral hypothalamus, as proTRH mRNA with this
probe, has been established in previous publications showing the
absence of hybridization in the hypothalamus with a noncomplementary
probe transcribed from the same 1241-bp fragment, a single hybridizing
band of approximately 1.6 kb by Northern hybridization corresponding to
the expected size of proTRH mRNA in RNA extracts of the PVN, and an
identical distribution of hybridized cells in the brain with a
different complementary probe recognizing the 3' untranslated region of
proTRH mRNA (11, 20, 21). Hybridization was performed under plastic
coverslips in buffer containing 50% formamide, a 2-fold concentration
of standard sodium citrate, 10% dextran sulfate, 0.25% BSA, 0.25%
Ficoll 400, 0.25% polyvinylpyrrolidone 360, 250 mM Tris
(pH 7.5), 0.5% sodium pyrophosphate, 0.5% SDS, 250 mg/ml denatured
salmon sperm DNA, and 6 x 105 cpm of the radiolabeled
probe, for 16 h at 55 C. Slides were dipped into Kodak NTB2
autoradiography emulsion (Eastman Kodak, Rochester, NY) and the
autoradiograms developed after 3 days of exposure at 4 C.
Image analysis
Autoradiograms of the PVN and, for comparison, the lateral
hypothalamus in the same tissue sections were visualized at x78 under
darkfield illumination with a Zeiss binocular microscope fitted with a
COHU solid-state TV camera (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 Data
Translation Quick Capture frame grabber board (Marlboro, MA) and
analyzed with a Quadra Macintosh computer using Image 1.52
(NIH). Background density points were removed by thresholding the
image, and integrated density values (density x area) of
hybridized neurons in the same region on each side of the PVN were
measured in each animal. Nonlinearity of radioactivity in the emulsion
was evaluated by comparing density values with a calibration curve
created from autoradiograms of known dilutions of the radiolabeled
probe immobilized on glass slides, in 1% gelatin, that had been
exposed and developed simultaneously with the in situ
hybridization autoradiograms. Values corresponding to the content of
proTRH mRNA in the PVN or lateral hypothalamus were calculated for each
animal by summing the integrated density values on each side of the PVN
from four consecutive sections, as previously described (22).
Hormone measurements
Plasma T3, T4, and TSH concentrations
were measured by RIA. Materials for the TSH RIA were provided by the
NIADDK National Hormone and Pituitary Program (Baltimore, MD) using
NIDDK rat TSH RP-2 as the standard. Plasma T3 and
T4 levels were measured with specific RIAs using antiserum
from Ventrex (Portland, ME) and [125I]-labeled
T3 or T4 obtained from New England Nuclear
(Boston, MA). Equilibrium dialysis was employed to determine the
fraction of T4 and T3 in plasma that was free.
The details of the assay have been reported previously (23). The COBRA
500 program was used for data reduction and calculation of the RIA
results.
Statistical analysis
Results are presented as means ± SEM.
Statistical significance between control and experimental groups was
determined by ANOVA, followed by Student-Newman-Keuls multiple
comparisons test. Differences were considered to be significant at
P < 0.05.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Results of plasma thyroid hormone and TSH determinations are shown in
Table 1
. Table 1 also shows data for the free
(nonprotein-bound) T4 and free T3 fractions in
plasma, as determined by equilibrium dialysis. As expected, plasma
T4 and T3 concentrations were reduced
significantly in fasted rats. In contrast, leptin had a profound
influence on the effect of fasting on plasma total and free thyroid
hormone concentrations. Serum T4 concentrations were only
slightly lower in fasted rats that were treated with leptin, compared
with fed rats, and serum free T4 concentrations in
leptin-treated fasted rats were actually higher than in fed rats.
Similarly, whereas serum total and free T3 were
significantly lower in fasted than in fed rats, fasted rats treated
with leptin had plasma T3 concentrations comparable with
those of fed rats. Plasma free T4 and free T3
concentrations, calculated by multiplying total plasma concentrations
by the free fraction, showed that fasting was associated with an
increase in the free fraction of T4 but not in the free
fraction of T3. The increase in the free T4
fraction was not statistically different in fasted rats that received
leptin, compared with those not treated with leptin. Mean plasma TSH
concentrations were slightly lower in fasted, compared with fed rats or
fasted leptin-treated rats, but differences among the groups were not
significant.
|
, A and B).
ProTRH-producing neurons were located primarily in the medial and
periventricular subdivisions of the PVN underlying the third ventricle
in midportions of the PVN (Fig. 1A) and clustered into a dense network
of cells in a triangular configuration in the medial parvocellular
subdivision of the PVN in more caudal portions of the nucleus (Fig. 1B). Intense hybridization was present also in adjacent neurons in the
lateral hypothalamus (Fig. 2).
|
|
, C and D). No
apparent reduction in hybridization signal over neurons in the lateral
hypothalamus was noted (Fig. 2, A and B). In contrast, fasted animals
receiving leptin showed a hybridization pattern over PVN neurons that
seemed identical to the fed animals (Fig. 1, E and F). No differences
in the intensity of the hybridization signal were noted in the lateral
hypothalamus (Fig. 2C).
By image analysis, the total density value for proTRH mRNA in the PVN
in fasted animals was reduced to approximately 62% of fed animals but,
after leptin administration, was restored to normal (Fig. 3A). Density values of the lateral hypothalamus in fed,
fasted, and fasted animals receiving leptin were unchanged (Fig. 3B).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
In response to environmental stressors and under certain pathological conditions, however, the hypothalamic-pituitary-thyroid axis rapidly readjusts its set point for feedback regulation by thyroid hormone, presumably in a way that is beneficial to the survival of the organism under these adverse circumstances. Cold exposure, for example, causes elevation of thyroid hormone levels, but it is associated also with increased expression of proTRH in hypophysiotropic neurons in the PVN and increased secretion of TSH (31, 32, 33, 34, 35), presumably as an adaptive response, to increase thermogenesis. Conversely, during fasting or infection, there is a fall in thyroid hormone levels, but a reduction in proTRH mRNA, in the PVN and inappropriately low or normal levels of plasma TSH (1, 2, 3, 4, 5, 6, 7, 8, 9, 36), presumably as an adaptive response to reduce thermogenesis and preserve nitrogen stores (37, 38, 39). The signals that override the normal physiological control mechanism of feedback regulation by thyroid hormone on hypophysiotropic proTRH neurons and reset the thyrostat in these PVN neurons are poorly understood. On the basis that the systemic administration of leptin, a fat cell-derived protein with important effects in mediating energy conservation (40), restored plasma levels of thyroid hormone to normal in fasting mice (16), we raised the possibility that the concentration of leptin in the circulation may be an important signal that establishes the set point for feedback regulation by thyroid hormone on these hypophysiotropic proTRH neurons. To begin to test this hypothesis, we determined whether leptin has a central action on proTRH-producing neurons in the PVN to regulate its biosynthesis.
As noted in previous studies (1, 2, 3, 4, 5, 6, 7, 8, 9), we observed also that fasted results in a significant decrease in plasma total and free T4 and T3 levels, a small (although insignificant) reduction in plasma TSH, and a significant reduction in proTRH mRNA in the PVN. Systemic administration of leptin to the fasted animals, however, prevented the fall in total and free T3 levels, whereas total T4 approached normal, and free T4 actually exceeded, the normal values in fed animals. As observed for total and free thyroid hormone levels, the systemic administration of leptin also prevented the reduction in proTRH mRNA in the PVN, resulting in levels that were not significantly different from the fed animals. This effect was specific for proTRH-synthesizing neurons in the PVN, because no effects of leptin were observed on adjacent proTRH-producing neurons in the lateral hypothalamus that do not have a hypophysiotropic function (41). These data demonstrate that leptin has a potent action on the hypothalamic-pituitary-thyroid axis in fasting animals to restore the reduced thyroid hormone levels to normal by increasing the biosynthesis of hypophysiotropic proTRH. By inference, therefore, the reduction in circulating thyroid hormones that occurs with fasting, simultaneously with a fall in leptin levels (17, 18), may be caused by an effect of falling plasma leptin levels to decrease the set point (increase the sensitivity) for feedback regulation of thyroid hormone on proTRH hypophysiotropic neurons.
In contrast, fasting was associated with an increase in the free fraction of T4, but not the free fraction of T3, as demonstrated by equilibrium dialysis. This finding was noted regardless of whether fasted rats received leptin. Fasting has complex, gender-influenced effects on serum thyroid hormone-binding proteins (42). Serum transthyretin, a major thyroid hormone-binding protein in the rat, declines during fasting, whereas T4-binding globulin, present in only trace levels in the fed rat, becomes clearly detectable. The lack of an effect of leptin on the fasting-induced changes in the free, nonprotein-bound plasma T4 fraction suggests that leptin may not influence the effect of fasting on plasma thyroid hormone-binding proteins.
Although the decline in plasma TSH in fasted rats was not significant, the absence of a TSH rise in the presence of the substantial decline in free thyroid hormone levels is consistent with central hypothyroidism. TRH has an important role in the glycosylation of TSH, such that a reduction in TRH leads to TSH with less complex carbohydrate structures and reduced bioactivity that can be restored by TRH administration (43, 44, 45). Similarly, in man, hypothalamic hypothyroidism often is characterized by normal, or even slightly elevated, serum TSH concentrations (46) and, as demonstrated by Beck-Peccoz et al. (47), is associated with reduced TSH bioactivity and decreased receptor activity on thyroid membranes. It seems likely, therefore, that the biological activity of TSH in fasted animals is reduced because of a fall in pituitary portal blood concentrations of TRH. Leptin administration, in turn, probably restores TSH bioactivity by blocking the effects of fasting on the biosynthesis of proTRH.
The mechanism(s) by which falling leptin levels reduce proTRH gene expression in the PVN requires further study, but several possibilities should be considered. The first is that leptin exerts direct effects on proTRH neurons, after entering the PVN, through its rich vascular supply (48). Banks et al. (49) have shown recently that leptin can be transported efficiently across the blood brain barrier from the systemic circulation by a saturable mechanism, which (given the large size of the protein) indicates the presence of an active transport system. Receptor autoradiography (49, 50, 51, 52) and the distribution of leptin receptor mRNA by in situ hybridization histochemistry (19), however, indicate that the PVN is not a site for leptin binding in the brain. Nevertheless, leptin binding has been observed in the median eminence (49), the point of termination of proTRH-producing neurons in the PVN, raising the possibility that leptin could have receptors on the axon terminals of these neurons and thereby influence the secretion of proTRH-derived peptides into the portal circulation.
Leptin may affect proTRH gene expression indirectly through effects on the hypothalamic-pituitary-adrenal (HPA) axis. When administered into the cerebrospinal fluid, leptin is reported to increase CRH gene expression in the PVN (19). Because reciprocal synaptic interactions between CRH and proTRH neurons in the PVN have been observed by electron microscopy (53), it is possible that CRH could mediate the effects of leptin on hypophysiotropic proTRH neurons via these interactions. CRH inhibits TRH release from rat hypothalamus in culture (54), however, which would be contrary to the observation that leptin administration to fasted animals increases proTRH mRNA in the PVN. A more important effect of leptin on the HPA axis may be seen in the association between elevated plasma corticosterone levels and low leptin levels during fasting (55, 56, 57) and the ability of systemically administered leptin to attenuate the fasting-induced rise in corticosterone (16). This indicates that the rise in corticosterone during fasting may be mediated by falling levels of leptin, although the locus for its action on the HPA axis is not known. Because glucocorticoids have a cell-specific effect to reduce proTRH mRNA levels in the PVN (58), the fasting-induced suppression of proTRH gene expression and rescue by leptin administration may be indirect, associated with leptin mediated changes in circulating corticosterone levels. Indeed, van Haasteren et al. (9) have reported that in a substrain of female Wistar rats (R-Amsterdam), the fasting associated reduction in proTRH mRNA in the PVN can be altered if the rise in corticosterone is prevented by adrenalectomy and replacement with corticosterone to maintain normal basal plasma concentrations. Glucocorticoids are not likely the only mechanism to explain changes in the hypothalamic-pituitary-thyroid axis during fasting, however, because in van Haasteren’s study, fasting in adrenalectomized-corticosterone replaced rats still resulted in a fall in circulating thyroid hormone levels (9). In addition, substantial doses of glucocorticoids are required to achieve only modest reductions in proTRH mRNA in PVN neurons, and these doses are associated with weight loss (58).
One of the most important recognized actions of leptin is its role in the regulation of NPY gene expression in the hypothalamus (59). During fasting, when leptin levels are low (17, 18), arcuate nucleus NPY gene expression is markedly increased (60, 61, 62). Conversely, the systemic administration of leptin results in pronounced inhibition of NPY gene expression in the arcuate nucleus (16, 59, 63) and has been proposed by Glaum et al. (64), on the basis of their electrophysiological studies on hypothalamic slices, to reduce the activity of NPY-producing neurons in the arcuate nucleus and decrease the release of NPY in the PVN. The arcuate nucleus contains a high density of leptin receptor mRNA (19), indicating that leptin can have a direct, central action on NPY production in this region of the brain. Because NPY-producing neurons in the arcuate nucleus project heavily to the PVN (65) and injections of NPY into the PVN increases food intake (66), it is presumed that leptin signals the PVN about feeding and body weight by way of NPY-containing axonal projection pathways originating in the arcuate nucleus. NPY-containing axon terminals also make numerous synaptic contacts with proTRH-producing neurons in the PVN (67), which we now believe arise primarily from neurons in the arcuate nucleus (Légrádi and Lechan, unpublished observations). The possibility that leptin could modulate proTRH gene activity in the PVN via direct actions on NPY neurons in the arcuate nucleus, therefore, seems particularly attractive and would link the regulation of thyroid thermogenesis and feeding behavior to a single anatomical pathway. As we have hypothesized that NPY may be inhibitory to proTRH neurons on the basis of electron microscopic characteristics of the synaptic contacts between NPY-containing axon terminals and proTRH perikarya and dendrites (67), we would propose that when leptin levels fall, NPY gene expression is disinhibited, resulting in the increased release of NPY in the PVN. This increase would simultaneously exert effects on feeding behavior and lower the threshold for thyroid hormone feedback inhibition on proTRH gene expression. Nevertheless, mice with targeted deletion of the NPY gene have recently been shown to have a fall in T4 during a 48-h fast that is indistinguishable from control animals (J Erickson, R Ahima, G. Hollopeter, J. Flier, and R. Palmiter, submitted), indicating that other targets capable of mediating a central action on hypophysiotropic proTRH neurons must also exist.
Cytokines, responsible for many of the manifestations of infection, also are well recognized to result in low circulating thyroid hormone levels and inappropriately low or normal levels of TSH, resulting in a disorder commonly referred to in man as the sick euthyroid syndrome (36). Both IL-1 and TNF cause significant reductions in TSH levels in man after systemic administration (68, 69) and reduce the content of TRH or proTRH mRNA in the hypothalamus of experimental animals (70, 71). This raises the possibility that the effects of falling leptin levels on proTRH gene expression in the PVN could be mediated by activation of the cytokine system peripherally or in the brain. Endotoxin and cytokines induce the expression of leptin (72), however, suggesting that the effect of cytokines on the hypothalamic-pituitary-thyroid axis may occur by a mechanism independent of leptin.
In conclusion, we have observed that the fasting-induced reduction in proTRH mRNA in hypophysiotropic neurons of the hypothalamic PVN can be prevented by the systemic administration of leptin. These findings indicate that the fall in circulating leptin levels may act as the critical signal to hypophysiotropic neurons in the PVN to reset the set point for feedback regulation of proTRH gene expression by thyroid hormone. This mechanism would inhibit proTRH gene expression in the PVN during fasting, when circulating thyroid hormone levels are low, and by reducing thyroid thermogenesis, act in a coordinated fashion with other homeostatic mechanisms to allow adaptation to starvation.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Received January 27, 1997.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
(cachectin).
Endocrinology 125:76–84[Abstract]
This article has been cited by other articles:
 |
|
 |
|
  R. L. Araujo, B. M. de Andrade, A. S. P. de Figueiredo, M. L. da Silva, M. P. Marassi, V. dos Santos Pereira, E. Bouskela, and D. P Carvalho Low replacement doses of thyroxine during food restriction restores type 1 deiodinase activity in rats and promotes body protein loss J. Endocrinol., July 1, 2008; 198(1): 119 - 125. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. E. Weiss and R. L. Brown Doctor . . . Could It Be My Thyroid? Arch Intern Med, March 24, 2008; 168(6): 568 - 569. [Full Text] [PDF]
|
|
|
|
|
|
S C P Dutra, E G Moura, A L Rodrigues, P C Lisboa, I Bonomo, F P Toste, and M C F Passos Cold exposure restores the decrease in leptin receptors (OB-Rb) caused by neonatal leptin treatment in 30-day-old rats J. Endocrinol., November 1, 2007; 195(2): 351 - 358. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Perello, R. C. Stuart, C. A. Vaslet, and E. A. Nillni Cold Exposure Increases the Biosynthesis and Proteolytic Processing of Prothyrotropin-Releasing Hormone in the Hypothalamic Paraventricular Nucleus via {beta}-Adrenoreceptors Endocrinology, October 1, 2007; 148(10): 4952 - 4964. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Knudson, G. M. Dick, and J. D. Tune Adipokines and Coronary Vasomotor Dysfunction Experimental Biology and Medicine, June 1, 2007; 232(6): 727 - 736. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. R Buff, N. T Messer IV, A. M Cogswell, D. A Wilson, P. J Johnson, D. H Keisler, and V. K Ganjam Induction of pulsatile secretion of leptin in horses following thyroidectomy J. Endocrinol., February 1, 2007; 192(2): 353 - 359. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Hashimoto, Y. Azuma, M. Kawasaki, H. Fujihara, E. Onuma, H. Yamada-Okabe, Y. Takuwa, E. Ogata, and Y. Ueta Parathyroid Hormone-Related Protein Induces Cachectic Syndromes without Directly Modulating the Expression of Hypothalamic Feeding-Regulating Peptides Clin. Cancer Res., January 1, 2007; 13(1): 292 - 298. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A Boelen, J Kwakkel, W M Wiersinga, and E Fliers Chronic local inflammation in mice results in decreased TRH and type 3 deiodinase mRNA expression in the hypothalamic paraventricular nucleus independently of diminished food intake J. Endocrinol., December 1, 2006; 191(3): 707 - 714. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. O. Huising, E. J. W. Geven, C. P. Kruiswijk, S. B. Nabuurs, E. H. Stolte, F. A. T. Spanings, B. M. L. Verburg-van Kemenade, and G. Flik Increased Leptin Expression in Common Carp (Cyprinus carpio) after Food Intake But Not after Fasting or Feeding to Satiation Endocrinology, December 1, 2006; 147(12): 5786 - 5797. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R THOMAS ZOELLER Collision of Basic and Applied Approaches to Risk Assessment of Thyroid Toxicants. Ann. N.Y. Acad. Sci., September 1, 2006; 1076: 168 - 190. [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]
|
|
|
|
|
|
A Boelen, J Kwakkel, X G Vos, W M Wiersinga, and E Fliers Differential effects of leptin and refeeding on the fasting-induced decrease of pituitary type 2 deiodinase and thyroid hormone receptor {beta}2 mRNA expression in mice. J. Endocrinol., August 1, 2006; 190(2): 537 - 544. [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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 P. Kok, F. Roelfsema, M. Frolich, A. E. Meinders, and H. Pijl Spontaneous Diurnal Thyrotropin Secretion Is Enhanced in Proportion to Circulating Leptin in Obese Premenopausal Women J. Clin. Endocrinol. Metab., November 1, 2005; 90(11): 6185 - 6191. [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]
|
|
|
|
|
|
|
