| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
ARTICLES |
Department of Medicine, Division of Endocrinology, Beth Israel Deaconess Medical Center (R.S.A., C.B., J.S.F.); and the Endocrinology-Hypertension Division, Brigham and Women’s Hospital, Harvard Medical School (S.O.), Boston, Massachusetts 02215
Address all correspondence and requests for reprints to: Jeffrey S. Flier, M.D., Beth Israel Deaconess Medical Center, Division of Endocrinology, Research North, 99 Brookline Avenue, Boston, Massachusetts 02215. E-mail: jflier{at}caregroup.harvard.edu
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Leptin administration prevents hyperphagia and obesity and restores neuroendocrine function in adult ob/ob mice (reviewed in Refs. 1, 2, 3), therefore implying that the brain is capable of responding to leptin during the postnatal period. To test the hypothesis that leptin influences brain development, we compared the expression of several neuronal and glial proteins among ob/ob, db/db, and leptin-resistant agouti (Ay/a) mice. We show that leptin deficiency or insensitivity to its action leads to decreased brain weight and protein content, elevated levels of growth-associated protein (GAP-43), and a reduction in the expression of several synaptic and glial proteins in the forebrains of ob/ob and db/db mice. Postnatal leptin administration increased brain weight, whole brain protein content, syntaxin-1, and synaptosomal-associated protein (SNAP-25) and decreased GAP-43 levels in ob/ob mice.
Locomotor activity, which was markedly reduced in ob/ob mice, was improved by leptin treatment. These findings are consistent with the view that leptin has diverse modulatory actions in the central nervous system in addition to its well known effects on energy homeostasis. Regulation of brain development by leptin may have important implications for the establishment of neural pathways for feeding, autonomic regulation and neuroendocrine function, and mechanisms linking impaired nutrition during the neonatal period with neural development.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
22 C) and humidity (30–35%) and were allowed ad
libitum access to chow and water. The experimental protocol
was in accordance with guidelines of the animal care and use committee
of the Beth Israel Deaconess Medical Center and Harvard Medical
School. ob/ob and db/db mice received daily ip injections of recombinant murine leptin (Eli Lilly & Co., Indianapolis, IN) at a dose of 1 µg/g BW in 100 µl saline or vehicle alone starting from age 4 and 8 weeks, respectively, until age 10 weeks. Lean littermates were injected with saline. Body weight was measured daily, and the dose of leptin was adjusted every third day. Injections were performed between 0800–1000 h of the light cycle. To determine whether leptin’s effects were mediated indirectly by an increase in thyroxine (T4) and a decrease in glucocorticoids during the postnatal period (12, 13), groups of 4- and 8-week-old ob/ob and db/db mice were injected daily with 1 µg L-T4 for 2 weeks or with 2 µg/g RU486 (14, 15). Treatment with RU486 or a combination of RU486 and L-T4 was discontinued after 1 week because of increased mortality.
Effect of leptin on hormone levels and synaptic and glial
proteins
Groups of mice were killed at various ages by rapid carbon
dioxide inhalation, and corticosterone, T4,
insulin and leptin were measured by RIA (12, 16). Plasma glucose was
measured with a glucose oxidase assay (Sigma Chemical Co.,
St. Louis, MO). Brains were weighed, and the neocortex, hippocampus,
striatum, hypothalamus, cerebellum, and brain stem were dissected,
frozen rapidly in liquid nitrogen, and stored at -80 C. Brain
homogenates and membrane-enriched fractions were prepared (17, 18), and
protein concentration was measured using a Bio-Rad DC Protein Assay kit
(Bio-Rad Laboratories, Inc., Hercules, CA).
For synaptic proteins and glial fibrillary acidic protein (GFAP), 5- to 10-µg protein aliquots were electrophoresed in 10% SDS-polyacrylamide gels and transferred to nitrocellulose. Western blotting was carried out with specific antibodies, and proteins were detected with peroxidase-conjugated secondary antibodies and enhanced chemiluminescence (Amersham, Arlington Heights, IL). Antibodies were obtained from Sigma Chemical Co. (St. Louis, MO), Chemicon (Temecula, CA), and Transduction Laboratories, Inc. (Lexington, KY) and were used at the following dilutions: GAP-43, 1:4000; syntaxin-1/HPC1, 1:2000; SNAP-25, 1:1000; synaptophysin, 1:3000; synaptotagmin, 1:2000; synaptobrevin, 1:3000; and GFAP, 1:1000. Myelin proteins were extracted as described previously (19, 20), separated by electrophoresis on 15% SDS-polyacrylamide gels, and detected by Western blotting. Specific antibodies to myelin basic protein (MBP), proteolipid protein (PLP), and 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNP) were obtained from Chemicon and were used at dilutions of 1:2500, 1:1000, and 1:500, respectively.
The relative abundance of synaptic and glial proteins was measured by laser densitometry of autoradiograms (Molecular Dynamics, Inc., Sunnyvale, CA). Integrated densities of the following protein bands recognized by specific antibodies were measured and taken to represent the relative quantities of the respective proteins: GAP-43 (43 kDa), syntaxin-1 (35 kDa), synaptophysin (38 kDa), SNAP-25 (25 kDa), synaptobrevin (18 kDa), synaptotagmin (65 kDa), GFAP (50 kDa), MBP (21 kDa), PLP (25 kDa), and CNP (48 kDa). A linear relationship with r values ranging from 0.9–0.95 was established between the density of immunostained bands for respective proteins and sample protein values between 5–30 µg (data not shown). Immunoblot analysis revealed similar levels of synaptophysin levels within specific brain regions in wild-type and mutant mice. Moreover, synaptophysin levels did not change with age (4–10 weeks) or leptin treatment and were therefore useful as an internal control for protein loading. The effect of leptin on the levels of GAP-43 and synaptic and glial proteins was determined by ANOVA and Fisher protected least protected difference test; P < 0.05 was considered significant.
Morphological studies
Adult ob/ob, db/db, and wild-type mice,
aged 10 and 20 weeks, respectively (n = 3/group), were deeply
anesthetized with ip sodium pentobarbital injection and perfused
transcardially with PBS, followed by 10% neutral buffered formalin.
Brains were allowed to remain in the skull for 2 h and then were
immersed in the same fixative at 4 C for 3 days. After cryoprotection
in 10% PBS-sucrose, 40-µm coronal sections were cut on a sliding
microtome and processed for silver staining (21) (FD Neurotechnologies,
Elicott City, MD). Adjacent sections were stained with thionin. The
sections were examined under brightfield optics using a Zeiss Axioskop
microscope (Carl Zeiss, New York, NY). Neurons undergoing
degeneration appeared black, whereas normal neurons appeared golden
yellow.
Brain sections corresponding to bregma levels -1.46 and -1.82 mm, i.e. Figs. 43 and 46 in the atlas of Paxinos and Franklin (22), were selected, matched, and analyzed by an observer blinded to the experiment. Silver-stained (black) cells were counted with a grid reticule and x10 objective lens in the parietal cortex and hippocampus in each hemisphere, and average counts per region were determined. Statistical differences between groups were analyzed by t test; P < 0.05 was considered significant.
Behavior observation
Locomotor activity in a novel environment was assessed with an
open field test (23). Testing was carried out between 1300–1500 h in
three clear plastic cages, with dimensions of 45 cm x 24 cm
x 22 cm containing a paper floor grid, by an observer who was blinded
to the treatment protocol. The mice were placed simultaneously in
individual cages, and after allowing 1 min for acclimation, they were
observed sequentially for 1-min periods for a total of 10
observations/test session. Mice were scored for walking
(i.e. number of floor grid lines crossed), climbing,
rearing, and grooming. Locomotor activity was defined as the sum of the
above behaviors during the test period. After measuring baseline
activity, ob/ob mice received daily ip injections of leptin
(1 µg/g BW) or saline starting from 4 weeks of age. Lean littermates
were injected with saline. Exploratory behavior was measured weekly in
age-matched saline- and leptin-treated mice. The potential interaction
between obesity and exploratory behavior was assessed further by
comparing activity scores between obese
Ay/a mice and their lean
littermates.
The effects of leptin on body weight and locomotor activity in ob/ob mice were determined by ANOVA and Fisher’s protected least significant difference test. Differences in body weight and locomotor activity between obese Ay/a mice and lean controls were analyzed by t test; P < 0.05 was considered significant.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
compares body weight,
hormone levels, and brain weight among ob/ob,
db/db, and agouti (Ay/a)
mice. Obesity in both ob/ob and db/db mice was
associated with elevated levels of corticosterone. Insulin levels were
elevated 10- and 5-fold in ob/ob and
Ay/a mice, respectively. Although
there was a trend toward lower T4 levels in
ob/ob and db/db mice compared with lean
littermates, the difference was not statistically significant.
Corticosterone and T4 levels were normal in
Ay/a mice.
|
). The
total brain protein content was 10% lower in 4-week-old
ob/ob mice (46.5 ± 2.5 mg) compared with that in
wild-type mice (41.5 ± 1.5 mg; P = 0.03). There
was a significant decrease in brain protein content by 14% in
10-week-old ob/ob mice (Table 1). Six weeks of leptin
treatment initiated at age 4 weeks resulted in a significant increase
in brain weight and total protein content in ob/ob mice
(Table 2). However, leptin treatment for
up to 2 weeks did not alter brain weight or total protein content when
initiated in 8-week-old ob/ob mice (Table 2). Brain weight
and protein content were significantly reduced at 4 weeks (data not
shown) and 10 weeks in db/db mice (Table 1). Leptin
treatment initiated at either 4 or 8 weeks did not affect brain weight
and protein content in db/db mice. There was no difference
in brain weight and total protein concentration between
Ay/a and wild-type mice (Table 1).
|
) and hippocampus of 20-week-old
ob/ob (Fig. 1) and db/db (micrograph not shown)
mice. The number of silver-stained cells did not change significantly
from 10–20 weeks of age or in response to leptin treatment.
|
) and other brain regions between
Ay/a and wild-type mice. In contrast,
expression of GAP-43 and synaptic proteins was differentially regulated
by leptin in ob/ob and db/db mice (
Figs. 2–4).
GAP-43 was elevated 3-fold in the neocortex (Fig. 3A), striatum, and hippocampus (data not
shown) of ob/ob and db/db mice. Daily leptin
injection at a dose of 1 µg/g BW initiated at 4 weeks decreased
GAP-43 expression in the neocortex (Figs. 3A and 4A), hippocampus, and
striatum of ob/ob mice, but did not affect GAP-43 levels in
db/db mice (Fig. 3A).
|
|
|
, B–D),
hippocampus, and hypothalamus of ob/ob mice. For example,
syntaxin-1, SNAP-25, and synaptobrevin were reduced significantly by
10–30% in the neocortex of 4-week-old ob/ob mice and
decreased further to 20–40% of control levels by age 10 weeks (Fig. 3, B–D). Leptin treatment restored syntaxin 1 (Figs. 3B and 4C) and
SNAP-25 (Fig. 3C), but did not affect synaptobrevin (Fig. 3D).
Expression of syntaxin-1, SNAP-25, and synaptobrevin was also decreased
in the neocortex (Figs. 2B and 3, B–D), hippocampus, and hypothalamus
of db/db mice and was not altered by age or leptin
treatment. Synaptophysin and synaptotagmin levels were normal in
ob/ob and db/db mice (Figs. 2C, 3, E and F, and
4D).
Regulation of glial proteins by leptin
There was no difference in the expression of glial proteins
between Ay/a and wild-type mice (data
not shown). Furthermore, the expression of glial proteins did not
change with age (4–10 weeks) in wild-type and mutant mice (data not
shown). Figures 4 and 5 illustrate the effects of leptin
deficiency and leptin treatment on glial proteins. GFAP, MBP, and PLP
were reduced in the neocortex (Fig. 5, A and C), striatum (Fig. 5B),
and hippocampus of ob/ob and db/db mice. There
was normal expression of the 21-kDa isoform of MBP in cerebellar (Fig. 5A) and brain stem extracts from ob/ob and db/db
mice; however, a 35-kDa band that was localized in wild-type mice was
clearly deficient in the cerebellum of ob/ob and
db/db mice (Fig. 5A). GFAP and PLP levels were normal in the
cerebellum and brain stem (data not shown).
|
) and other brain
regions. Daily leptin treatment from 4–10 weeks of age did not affect
GFAP and myelin proteins in ob/ob (Fig. 5, B and C) and
db/db mice. As glucocorticoids and thyroid hormone are
regulated by leptin (12, 13, 16) and, in turn, regulate the synthesis
of glial proteins (19, 20, 24, 25, 26), we determined the effect of
T4 treatment and/or glucocorticoid blockade on
GFAP and myelin proteins in ob/ob and db/db mice.
Although serum T4 levels rose to 8–12 µg/dl
after 2 weeks of treatment in 4-week-old ob/ob mice, myelin
proteins and GFAP were not altered. Similarly, blockade of
glucocorticoids with RU486 from 4–5 weeks of age did not affect glial
proteins (data not shown).
Effect of leptin on locomotor activity
Locomotor activity was decreased in ob/ob mice at all
ages compared with that in lean controls (Fig. 6, A and B). Of the four behavioral
parameters examined, walking, climbing, and rearing were the most
affected by leptin deficiency. Locomotor activity was 50% lower in
4-week-old ob/ob mice compared with that in lean
littermates. There was no further reduction in activity in
ob/ob mice within the first week (4–5 weeks of age) despite
an increase in body weight by 25% (P < 0.05).
However, by age 10 weeks body weight had increased by 80%, whereas
locomotor activity decreased by 50%. Prevention of weight gain in
ob/ob mice by daily leptin injection resulted in an increase
in locomotor activity by 70% within 1 week of initiation of treatment
(Fig. 6, A and B). In contrast with that in ob/ob mice,
locomotor activity was not affected by obesity in
Ay/a mice (Fig. 6C).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Development of the central nervous system is influenced by hormones during the postnatal period. For example, glucocorticoids regulate neuronal and glial proliferation and differentiation, whereas thyroid hormone and GH regulate several aspects of postnatal brain development, notably myelination (19, 20, 24, 25, 26). The widespread distribution of leptin targets in the brain and localization of leptin receptors in neurons as well as glia (29, 30, 31) is suggestive of direct regulation of neuronal and glial function by leptin. On the other hand, as leptin regulates the levels of glucocorticoids, thyroid hormone, and GH (12, 13, 16, 32), and these hormones are known to influence brain development (19, 20, 24, 25, 26), it is possible that the observed differences in the levels of neuronal and glial proteins between ob/ob and lean mice are at least in part an indirect result of leptin deficiency.
ob/ob and db/db mice had an immature pattern of expression of GAP-43 and components of the SNARE synaptic transport complex (33, 34, 35). GAP-43 is expressed at high levels during neonatal life and has been implicated in axogenesis (33, 34). There is marked reduction in GAP-43 after weaning; however, low levels persist in several brain regions in the adult brain and may play a role in synaptic plasticity (33, 34). ob/ob and db/db mice had elevated levels of GAP-43 and reductions in syntaxin-1, SNAP-25, and synaptobrevin. Leptin treatment normalized GAP-43, syntaxin-1, and SNAP-25 levels in ob/ob mice.
The functional implications of differential regulation of synaptic proteins by leptin are not known. As the level of synaptic proteins is likely to influence synaptic activity and hence neurotransmitter release, we speculate that abnormalities of synaptic transmission resulting from leptin deficiency may contribute to the complex and widespread central nervous system dysfunction observed in ob/ob mice. The discovery that leptin regulates neuropeptide Y release from brain slices through a calcium-dependent pathway supports of a role for leptin in synaptic transmission (36). Results from the current study showing a decrease in locomotor activity in ob/ob mice are in agreement with classic studies by Joosten and van der Kroon (37). Several lines of evidence argue against the idea that ob/ob mice are less active because they are morbidly obese. First, other genetically obese mice, e.g. agouti (Ay/a and Avy/a) and New Zealand obese (NZO) mice, are as active as their lean littermates (38). Second, decreased locomotor activity precedes the onset of morbid obesity in ob/ob mice (37, 39). Third, studies by Clark and Gay (40) have shown that ob/ob mice are less active than weight-matched normal mice. Although the improvement in locomotor activity as a result of leptin administration could be attributed in part to weight loss, it is conceivable that normalization of synaptic proteins levels in the neocortex and hippocampus by leptin may have enhanced locomotor activity by increasing motivational and other higher aspects of behavior. This hypothesis awaits further experimentation.
Leptin deficiency resulted in decreased levels of myelin proteins and GFAP in the forebrain of ob/ob mice. This finding is in agreement with previous studies showing decreased brain myelin content as well as abnormal myelin lipid composition in ob/ob mice (4, 8, 41). Abnormalities of myelin-associated enzymes have also been described in db/db mice (28). Our observation that levels of the myelin enzyme CNP are unchanged in ob/ob mice despite a marked reduction in brain myelin content is in agreement with a previous report (8), and supports the view that leptin deficiency affects myelin synthesis. The failure of leptin treatment initiated at age 4 weeks to increase myelin proteins and GFAP in ob/ob mice is not inconsistent with the regulation of glial proteins by leptin. Other metabolic hormones, such as glucocorticoids and thyroid hormone, influence brain maturation at different stages of development (26). For example, myelin proteins are decreased by thyroidectomy during the second postnatal week, but not in older mice (19). Thyroid hormone regulates the expression of myelin proteins at an earlier stage in the hindbrain of neonatal rodents compared with that in forebrain regions such as the striatum and neocortex (19, 20). Similarly, the phenotype of ob/ob mice, including decreased brain weight, is regulated by glucocorticoids during the postnatal period (42). Adrenalectomy at 4–5 weeks of age prevents the development of morbid obesity as well as a reduction in brain weight in ob/ob mice (42). The failure of daily injections of leptin, T4, and glucocorticoid blockade to normalize myelin proteins and GFAP in 4-week-old ob/ob mice could be explained by either the late timing or the short duration of treatment.
There are similarities between the phenotype of leptin-deficient and insensitive rodents and humans, such as hyperphagia, morbid obesity, decreased linear growth, central hypogonadism and hypothyroidism, and impaired sympathetic response (1, 27, 43, 44, 45). However, the limited data to date suggest that leptin deficiency does not lead to hypercortisolism in humans, and brain structure is reported to be normal on computerized tomography (44). Leptin deficiency causes compulsive eating in humans, but has not as yet been associated with psychomotor or learning abnormalities (43, 44, 45). The mechanisms underlying the species differences in the hypothalamic-pituitary-adrenal axis and brain morphology between leptin-deficient rodents and humans have yet to be determined and are important subjects for future research.
A role of leptin in development is further suggested by the expression of leptin by placenta (46, 47), widespread synthesis of leptin and leptin receptors in fetal tissues (47), and regulation of hemopoiesis by leptin (48). The ability of leptin to regulate brain weight, brain protein content, and several neuronal and glial markers supports the view that leptin is of fundamental importance to brain maturation at least in rodents. As with other metabolic hormones, leptin is likely to influence brain development at critical stages of the prenatal and early postnatal periods. A potential developmental role of leptin may be to serve as an important link between early nutrition and brain development.
|
Footnotes |
|---|
Received November 4, 1998.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-melanocyte-stimulating hormone in
genetically obese (ob/ob) mice during development. Proc Natl
Acad Sci USA 76:2077–2080This article has been cited by other articles:
 |
|
 |
|
  S. Seo, D.-F. Guo, K. Bugge, D. A. Morgan, K. Rahmouni, and V. C. Sheffield Requirement of Bardet-Biedl syndrome proteins for leptin receptor signaling Hum. Mol. Genet., April 1, 2009; 18(7): 1323 - 1331. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Srinivasan, P. Mitrani, G. Sadhanandan, C. Dodds, S. Shbeir-ElDika, S. Thamotharan, H. Ghanim, P. Dandona, S. U Devaskar, and M. S Patel A high-carbohydrate diet in the immediate postnatal life of rats induces adaptations predisposing to adult-onset obesity J. Endocrinol., June 1, 2008; 197(3): 565 - 574. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Ahima and M. A. Lazar Adipokines and the Peripheral and Neural Control of Energy Balance Mol. Endocrinol., May 1, 2008; 22(5): 1023 - 1031. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. J. Forhead, C. A. Lamb, K. L. Franko, D. M. O'Connor, F. B. P. Wooding, R. L. Cripps, S. Ozanne, D. Blache, Q. W. Shen, M. Du, et al. Role of leptin in the regulation of growth and carbohydrate metabolism in the ovine fetus during late gestation J. Physiol., May 1, 2008; 586(9): 2393 - 2403. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 F. Zhang, S. Wang, A. P. Signore, and J. Chen Neuroprotective Effects of Leptin Against Ischemic Injury Induced by Oxygen-Glucose Deprivation and Transient Cerebral Ischemia Stroke, August 1, 2007; 38(8): 2329 - 2336. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. G. Roseberry, T. Painter, G. P. Mark, and J. T. Williams Decreased Vesicular Somatodendritic Dopamine Stores in Leptin-Deficient Mice J. Neurosci., June 27, 2007; 27(26): 7021 - 7027. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. S. Ahima, Y. Qi, N. S. Singhal, M. B. Jackson, and P. E. Scherer Brain Adipocytokine Action and Metabolic Regulation Diabetes, December 1, 2006; 55(Supplement_2): S145 - S154. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Lechuga-Sancho, A. I. Arroba, L. M. Frago, C. Garcia-Caceres, A. D.-R. de Celix, J. Argente, and J. A. Chowen Reduction in the Number of Astrocytes and Their Projections Is Associated with Increased Synaptic Protein Density in the Hypothalamus of Poorly Controlled Diabetic Rats Endocrinology, November 1, 2006; 147(11): 5314 - 5324. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. N. Gorski, A. A. Dunn-Meynell, T. G. Hartman, and B. E. Levin Postnatal environment overrides genetic and prenatal factors influencing offspring obesity and insulin resistance Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2006; 291(3): R768 - R778. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. E Levin Metabolic imprinting: critical impact of the perinatal environment on the regulation of energy homeostasis Phil Trans R Soc B, July 29, 2006; 361(1471): 1107 - 1121. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Valerio, V. Ghisi, M. Dossena, C. Tonello, A. Giordano, A. Frontini, M. Ferrario, M. Pizzi, P. Spano, M. O. Carruba, et al. Leptin Increases Axonal Growth Cone Size in Developing Mouse Cortical Neurons by Convergent Signals Inactivating Glycogen Synthase Kinase-3beta J. Biol. Chem., May 5, 2006; 281(18): 12950 - 12958. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. V. Mobbs Fathead: The Gain in Brain Falls Mainly with Leptin Wane Endocrinology, February 1, 2006; 147(2): 645 - 646. [Full Text] [PDF]
|
|
|
|
|
|
J. Udagawa, R. Hashimoto, H. Suzuki, T. Hatta, Y. Sotomaru, K. Hioki, Y. Kagohashi, T. Nomura, Y. Minami, and H. Otani The Role of Leptin in the Development of the Cerebral Cortex in Mouse Embryos Endocrinology, February 1, 2006; 147(2): 647 - 658. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. G. Myers Jr., M. E. Patti, and R. L. Leshan Hitting the Target: Leptin and Perinatal Nutrition in the Predisposition to Obesity Endocrinology, October 1, 2005; 146(10): 4209 - 4210. [Full Text] [PDF]
|
|
|
|
 |
|
 J. A. Matochik, E. D. London, B. O. Yildiz, M. Ozata, S. Caglayan, A. M. DePaoli, M.-L. Wong, and J. Licinio Effect of Leptin Replacement on Brain Structure in Genetically Leptin-Deficient Adults J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 2851 - 2854. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. R. Castaneda, H. Jurgens, P. Wiedmer, P. Pfluger, S. Diano, T. L. Horvath, M. Tang-Christensen, and M. H. Tschop Obesity and the Neuroendocrine Control of Energy Homeostasis: The Role of Spontaneous Locomotor Activity J. Nutr., May 1, 2005; 135(5): 1314 - 1319. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
V. C. Russo, S. Metaxas, K. Kobayashi, M. Harris, and G. A. Werther Antiapoptotic Effects of Leptin in Human Neuroblastoma Cells Endocrinology, September 1, 2004; 145(9): 4103 - 4112. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. W. Rajala, Y. Qi, H. R. Patel, N. Takahashi, R. Banerjee, U. B. Pajvani, M. K. Sinha, R. L. Gingerich, P. E. Scherer, and R. S. Ahima Regulation of Resistin Expression and Circulating Levels in Obesity, Diabetes, and Fasting Diabetes, July 1, 2004; 53(7): 1671 - 1679. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. G. Bouret and R. B. Simerly Minireview: Leptin and Development of Hypothalamic Feeding Circuits Endocrinology, June 1, 2004; 145(6): 2621 - 2626. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. G. Bouret, S. J. Draper, and R. B. Simerly Trophic Action of Leptin on Hypothalamic Neurons That Regulate Feeding Science, April 2, 2004; 304(5667): 108 - 110. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. A. El-Haddad, M. Desai, D. Gayle, and M. G. Ross In Utero Development of Fetal Thirst and Appetite: Potential for Programming Reproductive Sciences, April 1, 2004; 11(3): 123 - 130. [Abstract] [PDF]
|
|
|
|
|
|
J. T. Smith and B. J. Waddell Leptin Distribution and Metabolism in the Pregnant Rat: Transplacental Leptin Passage Increases in Late Gestation but Is Reduced by Excess Glucocorticoids Endocrinology, July 1, 2003; 144(7): 3024 - 3030. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. E. Levin and A. A. Dunn-Meynell Maternal obesity alters adiposity and monoamine function in genetically predisposed offspring Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2002; 283(5): R1087 - R1093. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. C.L. Tou and C. E. Wade Determinants Affecting Physical Activity Levels In Animal Models Experimental Biology and Medicine, September 1, 2002; 227(8): 587 - 600. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. J. McCarthy, W. A. Banks, C. L. Farrell, S. Adamu, C. P. Derdeyn, A. Z. Snyder, R. Laforest, D. C. Litzinger, D. Martin, C. P. LeBel, et al. Positron Emission Tomography Shows that Intrathecal Leptin Reaches the Hypothalamus in Baboons J. Pharmacol. Exp. Ther., June 1, 2002; 301(3): 878 - 883. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. A. Ehrhardt, A. W. Bell, and Y. R. Boisclair Spatial and developmental regulation of leptin in fetal sheep Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2002; 282(6): R1628 - R1635. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Forhead, L. Thomas, J. Crabtree, N. Hoggard, D. S. Gardner, D. A. Giussani, and A. L. Fowden Plasma Leptin Concentration in Fetal Sheep during Late Gestation: Ontogeny and Effect of Glucocorticoids Endocrinology, April 1, 2002; 143(4): 1166 - 1173. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. A. Banks, J. E. Phillips-Conroy, C. J. Jolly, and J. E. Morley Serum Leptin Levels in Wild and Captive Populations of Baboons (Papio): Implications for the Ancestral Role of Leptin J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4315 - 4320. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Yamashita, J. Shao, T. Ishizuka, P. J. Klepcyk, P. Muhlenkamp, L. Qiao, N. Hoggard, and J. E. Friedman Leptin Administration Prevents Spontaneous Gestational Diabetes in Heterozygous Leprdb/+ Mice: Effects on Placental Leptin and Fetal Growth Endocrinology, July 1, 2001; 142(7): 2888 - 2897. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Fantuzzi and R. Faggioni Leptin in the regulation of immunity, inflammation, and hematopoiesis J. Leukoc. Biol., October 1, 2000; 68(4): 437 - 446. [Abstract] [Full Text]
|
|
|
|
 |
|
 W. A. Banks, C. M. Clever, and C. L. Farrell Partial saturation and regional variation in the blood-to-brain transport of leptin in normal weight mice Am J Physiol Endocrinol Metab, June 1, 2000; 278(6): E1158 - E1165. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. V. Zlokovic, S. Jovanovic, W. Miao, S. Samara, S. Verma, and C. L. Farrell Differential Regulation of Leptin Transport by the Choroid Plexus and Blood-Brain Barrier and High Affinity Transport Systems for Entry into Hypothalamus and Across the Blood-Cerebrospinal Fluid Barrier Endocrinology, April 1, 2000; 141(4): 1434 - 1441. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
