help button home button Endocrine Society Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology, doi:10.1210/en.2003-0369
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Elefteriou, F.
Right arrow Articles by Karsenty, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Elefteriou, F.
Right arrow Articles by Karsenty, G.
Endocrinology Vol. 144, No. 9 3842-3847
Copyright © 2003 by The Endocrine Society

Monosodium Glutamate-Sensitive Hypothalamic Neurons Contribute to the Control of Bone Mass

Florent Elefteriou, Shu Takeda, Xiuyun Liu, Dawna Armstrong and Gerard Karsenty

Department of Molecular and Human Genetics (F.E., S.T., X.L., G.K.), Bone Disease Program of Texas, and Department of Pathology (D.A.), Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Gerard Karsenty, M.D., Ph.D., Department of Molecular and Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030. E-mail: karsenty{at}bcm.tmc.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Using chemical lesioning we previously identified hypothalamic neurons that are required for leptin antiosteogenic function. In the course of these studies we observed that destruction of neurons sensitive to monosodium glutamate (MSG) in arcuate nuclei did not affect bone mass. However MSG treatment leads to hypogonadism, a condition inducing bone loss. Therefore the normal bone mass of MSG-treated mice suggested that MSG-sensitive neurons may be implicated in the control of bone mass. To test this hypothesis we assessed bone resorption and bone formation parameters in MSG-treated mice. We show here that MSG-treated mice display the expected increase in bone resorption and that their normal bone mass is due to a concomitant increase in bone formation. Correction of MSG-induced hypogonadism by physiological doses of estradiol corrected the abnormal bone resorptive activity in MSG-treated mice and uncovered their high bone mass phenotype. Because neuropeptide Y (NPY) is highly expressed in MSG-sensitive neurons we tested whether NPY regulates bone formation. Surprisingly, NPY-deficient mice had a normal bone mass. This study reveals that distinct populations of hypothalamic neurons are involved in the control of bone mass and demonstrates that MSG-sensitive neurons control bone formation in a leptin-independent manner. It also indicates that NPY deficiency does not affect bone mass.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
LESION OF NEURONAL populations through the use of neurotoxins has been successfully used for nearly 60 yr in the study of central homeostatic functions. This approach established the existence of hypothalamic centers controlling satiety and hunger in the 1950s (1, 2, 3, 4). More recently, we have used this approach as an initial step in the identification of hypothalamic neurons and neuronal networks involved in the control of bone mass (5). This led us to demonstrate that gold thioglucose (GTG)-sensitive neurons, located primarily in the ventromedial hypothalamus nuclei (VMH), negatively regulate bone formation and that GTG-sensitive neuronal structures are required for leptin antiosteogenic function. Indeed, destruction of GTG-sensitive neurons led to an increase in bone formation resulting in a high bone mass phenotype, and intracerebroventricular infusion of leptin in GTG-treated mice failed to reduce bone mass as it does in wild-type mice.

In the course of this study, we also used monosodium glutamate (MSG) treatment to identify potential antiosteogenic neurons in the arcuate nuclei. In contrast to GTG, MSG treatment of wild-type mice did not affect bone mass nor did it inhibit leptin antiosteogenic function in leptin-deficient (ob/ob) mice. These latter results established that MSG- sensitive neurons are not required for leptin antiosteogenic function. Nevertheless, we were surprised by the normal bone mass observed in MSG-treated mice because they develop a hypogonadism that should increase bone resorption and lead to osteopenia (3, 6). The normal bone mass of MSG-treated mice raised the hypothesis that MSG treatment may affect neurons controlling bone formation, although in a leptin-independent manner. Their destruction would induce an increase in bone formation that would compensate for the hypogonadism-induced increase in bone resorption. This is an important hypothesis because its verification would provide additional support for the existence of a central control of bone formation. To test this hypothesis, we analyzed bone formation parameters in MSG-treated animals before and after correction of their hypogonadism. We show here that the normal bone mass of MSG-treated mice is indeed accounted for by an increase in bone formation that counterbalances an increase in bone resorption. Given that neuropeptide Y (NPY) is one of the most abundant neuropeptides produced by arcuate neurons and that Y2 receptor-deficient mice have a high bone mass phenotype (7), we tested whether NPY deficiency affects bone formation in vivo. Surprisingly NPY-deficient mice have a normal bone mass, indicating that MSG-sensitive neurons regulating bone formation are distinct from NPY-expressing neurons.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animal treatments
Wild-type (C57BL/6J) mice were obtained from Jackson Laboratories (Bar Harbor, ME). NPY-deficient mice were kindly provided by Dr R. Palmiter (129SV/C57BL6 background). MSG lesioning was performed as previously described by daily sc injections of either PBS (Invitrogen Corp., Carlsbad, CA) or MSG (2 mg/g, Sigma, St. Louis, MO) to 2-d-old C57BL/6J female pups for 10 d. Mice were subsequently fed ad libitum after weaning and housed under normal light and dark cycle. As previously observed by others, 20% of pups died on MSG treatment (8). Among the surviving mice, 66% became obese (defined here with a body weight 20% superior to PBS-treated mice). 17ß-Estradiol pellets (Innovative Research of America, Sarasota, FL) delivering 0.15 µg of 17ß-estradiol per day were placed under anesthesia under dorsal sc space in 4-wk-old female mice at the time of puberty characterized by vaginal opening. At 3 months of age, animals were deeply anesthetized with isoflurane and bled by cardiac puncture for serum collection and hormone measurements. Bone formation rate (BFR) was measured by the calcein double-labeling method, which enable the measurement of the amount of new mineralized bone laid down per micrometer of bone surface per year (9). Calcein (Sigma) was administered twice ip at 0.125 mg/g of body weight dissolved in calcein buffer (0.15 M NaCl, 2% NaHCO3) at d 1 and 8, and mice were killed at d 10. All animal protocols were approved by the Animal Care Committee of Baylor College of Medicine.

Hormones and metabolites measurements
Estradiol serum levels were quantified using the third-generation RIA kit from DSL (Diagnostic Systems Laboratories, Webster, TX). FSH serum levels were determined by RIA using reagents provided by Dr. A. F. Parlow and the National Hormone and Peptide Program at the Ligand Assay and Analysis Core Laboratory (ligandcore@virginia.edu). Deoxypyridinoline cross-links and creatinine levels were measured in morning urines using the Pyrilinks-D and creatinine assay kits (Metra Biosystems Inc., Mountain View, CA).

Histological procedures
Brain was removed from the skull and fixed overnight in 10% buffered formalin phosphate at 4 C. Specimens were dehydrated in graded ethanol series, cleared in chloroform overnight, and embedded in paraffin. Six-micrometer sections were cut and stained with 0.1% cresyl violet using standard procedures. Immunohistochemistry was performed according to standard protocols (10). Antiprogesterone receptor monoclonal antibody (DAKO, Carpinteria, CA) and was used at 1/800 dilution following high-temperature steam antigen retrieval in EDTA (pH 8). The atlas of Paxinos and Franklin (11) was used for brain anatomical landmarks.

For bone histology, lumbar vertebrae were dissected, fixed 12 h in 4% paraformaldehyde/PBS, pH 7.3, dehydrated in graded ethanol series, and embedded in methyl methacrylate resin according to standard protocols (12). Seven-micrometer frontal sections were stained by von Kossa and counterstained by von Gieson for bone volume measurement. For osteoclast counting, adjacent 7-µm sections were stained for tartrate-resistant acid phosphatase (TRAP) activity and counterstained with Toluidine blue according to established protocol (13). Unstained 12-µm sections were analyzed for BFR measurements.

Histomorphometric measurements and statistical tests
Static and dynamic histomorphometric analyses were performed according to standard protocols (9) using the Osteomeasure analysis system (Osteometrics, Inc., Atlanta, GA). Six to eight animals were assigned per group and analyzed for bone histomorphometry at the end of the experiments. Data are reported in accordance with standard nomenclature (9) and are expressed as mean ± SD. Statistical significance was assessed by t test. P < 0.05 was considered statistically significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Spatial restriction of MSG-induced neuronal lesions
Two-day-old wild-type C57BL6 pups were treated for 10 d with PBS or MSG (2 mg/g) by sc injections. This treatment damages circumventricular neurons expressing the glutamate receptor and affects several homeostatic functions such as body weight and reproduction (4, 8, 14, 15). Food intake has been shown to be normal in MSG-treated mice (8), and we did not notice any abnormalities in our MSG-treated mice. However, fat pad weights of 3-month-old mice were significantly increased following this treatment, compared with lean PBS-treated mice (Fig. 1AGo). This phenotypic abnormality was used as a control of the efficacy of MSG treatment, and only MSG-treated obese mice (body weight more than 20% superior to control) were further analyzed.



View larger version (58K):
[in this window]
[in a new window]
  		FIG. 1. Spatial restriction of MSG-induced lesions. A, The fat pad weight of MSG-treated mice is markedly increased, compared with PBS-treated mice. B, Shematic representation of the hypothalamus (top panels), cresyl violet staining (middle panels), and immunohistochemistry for the progesterone receptor (bottom panels). The planes of brain sections are located -1.7 from bregma according to Paxinos’ reference atlas. MSG treatment markedly affected arcuate cell density and progesterone receptor expression (arrows). C, Cell count in arcuate (ARC) and VMH nuclei of PBS- and MSG-treated mice. MSG treatment markedly decreased arcuate cell number but not VMH cell number. Asterisks, Statistically significant differences between PBS- and MSG-treated groups (n = 6 per group, P < 0.05). Error bars, SD.

 
Brain histology was also performed to demonstrate the effectiveness of MSG treatment in each animal and to identify neurons affected by MSG treatment. Examination of cresyl violet-stained brain sections showed that MSG treatment led to the near disappearance of recognizable arcuate nuclei (Fig. 1BGo, middle panel). No other anatomical lesion could be identified anywhere else in the brain of MSG-treated mice. To provide a quantitative appreciation of the deleterious effect of MSG on hypothalamic neurons, cells were counted in the arcuate nuclei of PBS- and MSG-treated mice as well as in other areas of the hypothalamus. The total number of cells in the arcuate nuclei of MSG-treated mice was decreased by 75%, compared with PBS-treated mice (Fig. 1CGo). In contrast, MSG treatment did not significantly affect cell number in the VMH or other hypothalamic areas (Fig. 1CGo and data not shown), indicating that this treatment affects preferential neurons of the arcuate nuclei. To further demonstrate that neurons of the arcuate nuclei were the cells primarily affected by MSG treatment, we performed immunocytochemistry using an antibody against the progesterone receptor, a molecular marker of arcuate neurons (16, 17). Numerous neuronal cell bodies in the arcuate nucleus of wild-type mice were labeled. In contrast, such labeling could not be observed in arcuate neurons of MSG-treated mice (Fig. 1BGo, bottom panel).

Hypogonadism and normal bone mass in MSG-treated mice
MSG-treated mice have been previously reported to be sterile (3). Accordingly, we failed to obtain any progeny from MSG-treated mice. To obtain a more objective assessment of the hypogonadism of MSG-treated mice, we compared uterus weight and appearance from PBS-treated and MSG-treated mice. As can be seen in Fig. 3BGo, a marked atrophy and reduced weight characterized the uteri of MSG-treated mice. Consistent with this phenotypic abnormality, estradiol levels in MSG-treated mice were below the range of detection (data not shown). FSH serum level was not altered following MSG lesion (5.6 ± 1.4 ng/ml in PBS-treated mice vs. 7.2 ± 0.3 ng/ml in MSG-treated mice).



View larger version (20K):
[in this window]
[in a new window]
  		FIG. 3. Correction of MSG-induced hypogonadism. A, Mice were treated at 1 month of age with sc pellets releasing estradiol (E2, 0.15 µg/d) constantly for 2 months. B, The uterus of MSG-treated mice is characterized by its marked atrophy and decreased weight. In contrast, the uterus of MSG-treated E2-repleted mice is similar in shape and weight to the one of PBS-treated E2-repleted mice. Asterisk, Statistically significant difference between PBS- and MSG-treated mice and between MSG-treated and MSG-treated E2-repleted groups (n = 8 per group, P < 0.05).

 
An expected consequence of this hypogonadism should be a decreased bone mass because of a predominant increase in bone resorption parameters (18, 19). Surprisingly we did not observe a low bone mass phenotype in MSG-treated mice (5). To address this apparent contradiction, we embarked in a thorough histological and biochemical analysis of bone resorption and bone formation parameters in 3-month-old PBS- and MSG-treated mice. These analyses revealed a 30% increase in both the number of TRAP-positive osteoclasts per bone perimeter and TRAP-positive surface per bone surface in MSG-treated mice, compared with PBS-treated animals (Fig. 2AGo). Accordingly the elimination of urinary deoxypyridinoline (dpd), a degradation product of collagen fibers and a biomarker of bone resorption (20) was increased by 40% in MSG-treated mice, compared with PBS-treated mice (Fig. 2AGo). Taken together these two lines of evidence demonstrate the existence of an increase in bone-resorptive activity in MSG-treated mice, which is consistent with their hypogonadism.



View larger version (22K):
[in this window]
[in a new window]
  		FIG. 2. Bone resorption and bone formation parameters in PBS- and MSG-treated mice. A, TRAP- positive surface per bone surface (Oc.S./B.S.), number of TRAP-positive osteoclasts per bone perimeter (N.Oc./B.Pm.), and urinary dpd values are increased in MSG-treated mice, compared with PBS-treated mice. B, Osteoblast surface (Ob.S./BS) is not affected by MSG treatment, but bone formation rate (BFR/BS) is increased in MSG-treated mice, compared with PBS-treated mice. Asterisk, Statistically significant differences between control and MSG-treated groups (n = 7 per group, P < 0.05). Error bars, SD.

 
The normal bone mass of MSG-treated mice in the face of an increased bone resorption suggested the existence of compensatory increase in osteoblast activity or number. To test this hypothesis, we measured parameters of osteoblast activity in 3-month-old animals. Dynamic histomorphometric analyses following double labeling by calcein injections revealed a 21% increase of the BFR in MSG-treated mice, compared with PBS-treated mice (Fig. 2BGo). This increase in the BFR was not accompanied by an increase in osteoblast surface (Fig. 2BGo). These results indicate that destruction of MSG-sensitive neurons leads to an increased osteoblastic activity and that this increase is of sufficient amplitude to neutralize the elevated bone resorption observed in these mice.

High bone mass in eugonadic MSG-treated mice
On the basis of the results described above, we hypothesized that correction of the hypogonadism of MSG-treated mice should reverse their high osteoclastic activity and uncover a high bone mass phenotype. To test this hypothesis, MSG-induced hypogonadism was corrected by implantation of estradiol pellets delivering physiological doses (0.15 µg/d) of estradiol to 4-wk-old MSG-treated females. These implants continuously delivered estradiol for 2 months (Fig. 3AGo). This dose of estradiol in both PBS- and MSG-treated mice did not increase blood estradiol levels above values observed in nontreated mice (PBS-treated mice: 8.3 ± 2.4 pg/ml; PBS+E2-treated mice: 8.9 ± 2 pg/ml; MSG+E2-treated mice: 7.2 ± 1.9 pg/ml), nor did it increase the BFR of estradiol-treated mice, compared with PBS-treated mice (data not shown). This treatment did not significantly affect osteoblast number (number of osteoblasts per bone perimeter: 10.2 ± 1.1 in estradiol-treated mice vs. 12.5 ± 0.23 in PBS-treated mice).

Following estradiol treatment, the uteri of MSG-treated estradiol-repleted mice had a normal weight and were indistinguishable from the ones of PBS-treated estradiol-treated or nontreated mice (Fig. 3BGo). These results indicate that estradiol treatment rescued the hypogonadism of MSG-treated mice without any overt pharmacologic effect. The consequences of the correction of the hypogonadism on bone remodeling parameters were assessed by histomorphometric analyses. TRAP-positive osteoclast number per bone perimeter and TRAP-positive surface per bone surface were both significantly decreased in MSG-treated estradiol-repleted mice, compared with MSG-treated mice and were not significantly different from the one observed in PBS-treated estradiol-treated mice (Fig. 4AGo). Similarly, urinary dpd values returned within normal range following estradiol treatment in MSG-treated mice (Fig. 4A). These results demonstrate that estradiol could effectively reverse the increase in bone resorption parameters normally observed following MSG treatment. As a result of the normalization of their bone-resorptive activity, MSG-treated estradiol-repleted mice had a significantly higher bone mass than PBS-treated estradiol-treated mice or untreated mice because their BFR remained elevated (Fig. 4BGo and data not shown). This high bone mass phenotype was not accompanied by hyperinsulinism, indicating that serum insulin levels are not responsible for the increase in bone formation observed following MSG treatment (data not shown). Taken together, these results demonstrate directly that MSG-sensitive neurons, mostly located in the arcuate nuclei, do contribute to the control of bone formation.



View larger version (50K):
[in this window]
[in a new window]
  		FIG. 4. Normal bone resorption parameters (A) and increased bone mass (B) in eugonadic MSG-treated mice. A, Number of TRAP- positive osteoclasts per bone perimeter (N.Oc./B.Pm.), TRAP-positive surface per bone surface (Oc.S./B.S.), and urinary dpd values are decreased following estradiol (E2) administration to MSG-treated mice. Asterisk, Statistically significant difference between PBS- and MSG-treated groups (n = 8 per group, P < 0.05). Bullet, Statistically significant difference between MSG-treated and MSG-treated E2-repleted groups (n = 8 per group, P < 0.05). B, MSG-treated mice have the same bone volume over tissue volume (BV/TV) than PBS-treated mice. However, E2 treatment increases BV/TV of MSG-treated mice, compared with PBS-treated E2-repleted mice. Asterisk, Statistically significant difference between PBS-treated E2-repleted and MSG-treated E2-repleted groups (n = 8 per group, P < 0.05).

 
Normal bone mass in NPY-deficient mice
One of the most abundant neuropeptides synthesized by arcuate neurons is NPY, and NPY immunoreactivity is lost following MSG treatment (5, 21, 22). Moreover, long-term infusion of NPY decreases bone mass (23) and mice deficient in one of the receptors for NPY, the Y2 receptor, display a high bone mass phenotype (7). These observations led us to ask whether NPY was the neuropeptide mediating the bone-forming activity of MSG-sensitive neurons. To that end we analyzed NPY-deficient mice at 3 and 6 months of age. At each time point analyzed and regardless of their sex, NPY-deficient mice had a normal bone mass (Fig. 5Go). This result indicates that the regulation of bone formation exerted by MSG-sensitive neurons involves neurons distinct from neurons expressing NPY.



View larger version (101K):
[in this window]
[in a new window]
  		FIG. 5. Normal bone mass in NPY-deficient mice. Bone volume over tissue volume (BV/TV) is not affected at 3 months (A) and 6 months (B) of age in male NPY-deficient mice (n = 7 per group).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Following the path of the pioneering line of work that led to the identification of hypothalamic centers regulating energy metabolism, our studies are now leading to the identification of hypothalamic structures and pathways regulating bone mass homeostasis. In a previous work (23), we demonstrated that leptin inhibits bone formation via a hypothalamic relay and that this function required GTG- sensitive neurons located primarily in the VMH (5). In the present study, we analyzed another population of neurons independent of leptin antiosteogenic function and characterized by their sensitivity to MSG. We show here that the destruction of MSG-sensitive neurons induced a marked increase in the bone formation rate facing an elevated resorption rate secondary to MSG-induced hypogonadism. The net result is a normal bone mass, and normalization of MSG-induced bone resorption by long-term estradiol treatment uncovers the high bone mass of MSG-treated mice. MSG-sensitive neurons are dispensable to leptin antiosteogenic function (5), and NPY does not appear to be the neuropeptide mediating the antiosteogenic function of these neurons.

Several lines of evidence demonstrate that MSG-sensitive neurons controlling bone mass are located primarily in the arcuate nucleus. First, the pool of neurons constituting the arcuate nuclei observed on coronal brain sections disappeared following MSG treatment, but neurons in other areas of the hypothalamus were not affected. Cell counts confirmed that the number of remaining cells in the arcuate nuclei was drastically reduced following MSG treatment. Second, expression of molecular markers enriched in arcuate neurons, such as NPY (5) and progesterone receptor, was markedly reduced by MSG treatment, confirming the restricted loss of neurons in these nuclei.

We previously showed that GTG treatment in wild-type mice induced a 40% bone mass increase, reaching the bone volume observed in leptin-deficient mice. In contrast, MSG treatment with correction of MSG-induced high bone resorption led to a modest 16% increase in bone volume relative to PBS-treated estradiol-treated mice. Several possibilities can explain this relatively modest gain of bone mass following MSG lesion, compared with GTG lesion. MSG lesioning could affect multiple arcuate neuronal subpopulations that could have antagonistic effects on bone remodeling. One arcuate subpopulation could, for instance, regulate bone mass negatively and the other could regulate bone mass positively. Body weight has been shown to be regulated by such antagonistic populations of neurons such as the orexigenic NPY and agouti gene-related peptide-expressing neurons and the anorexigenic cocaine- and amphetamine-induced transcript- and proopiomelanocortin-expressing neurons (24). The consequence of MSG treatment would then be a bone phenotype of relatively small amplitude, similar to the one observed in the present study. This type of antagonistic effects following MSG lesioning has been proposed to explain the relatively mild body weight phenotype observed in MSG-treated mice (25). Alternatively, MSG treatment could affect only a single class of antiosteogenic neurons whose role would be minor, compared with the one played by GTG-sensitive neurons.

A recent study by Baldock et al. (7) demonstrated the involvement of Y2 receptor in the central control of bone mass. This finding and the observation that NPY infusion can induce bone loss (23) led us to explore the physiological role of NPY in the control of bone formation. Unlike Y2 receptor-deficient mice, NPY-deficient mice have a normal bone mass, suggesting that another member of this family of protein may be the ligand of Y2 receptor affecting bone mass. To date there is no information available about the role that other members of this family of proteins, such as peptide YY or pancreatic polypeptide Y, may have on bone metabolism. In light of the normal phenotype of the NPY-deficient mice, we hypothesize that the antiosteogenic effect of NPY described by Ducy et al. (23) may be explained by the high amount of NPY used in this experiment (75 ng/h). Although this is the amount used to affect food intake and body weight (26, 27, 28), the absence of bone abnormalities in NPY-deficient mice suggests that at this concentration NPY may have pharmacological effects.


   Acknowledgments
 
We are indebted to Dr. R. Palmiter (University of Washington, Seattle) for providing NPY-deficient mice, M. Starbuck and B. Antalffy for superb technical assistance, and P. Ducy for critical reading of the manuscript.


   Footnotes
 
This work was supported by NIH Grants DK58883 (to G.K.) and DK54480 (to D.A.) and National Aeronautics and Space Administration (NCC9-58, to G.K.), the "Fondation pour la Recherche Medicale" and the Children’s Nutrition Research Center (to F.E.), and the Arthritis Foundation (to S.T.). The Ligand Assay and Analysis Core Laboratory is supported by National Institute of Child Health and Human Development/National Institutes of Health through cooperative agreement U54HD28934.

F.E. and S.T. contributed equally to this work.

Abbreviations: BFR, Bone formation rate; dpd, deoxypyridinoline; GTG, gold thioglucose; MSG, monosodium glutamate; NPY, neuropeptide Y; TRAP, tartrate-resistant acid phosphatase; VMH, ventromedial hypothalamus nuclei.

Received March 24, 2003.

Accepted for publication June 2, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Waxler SH, Brecher G 1950 Obesity and food requirement in albino mice following administration of gold thioglucose. Am J Physiol 162:428–433[Free Full Text]
  2. Bray GA, York DA 1998 The MONA LISA hypothesis in the time of leptin. Recent Prog Horm Res 53:95–117
  3. Olney JW 1969 Brain lesions, obesity, and other disturbances in mice treated with monosodium glutamate. Science 164:719–721[Abstract/Free Full Text]
  4. Debons AF, Krimsky I, Maayan ML, Fani K, Jemenez FA 1977 Gold thioglucose obesity syndrome. Fed Proc 36:143–147[Medline]
  5. Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao L, Parker KL, Armstrong D, Ducy P, Karsenty G 2002 Leptin regulates bone formation via the sympathetic nervous system. Cell 111:305–317[CrossRef][Medline]
  6. Cenci S, Weitzmann MN, Roggia C, Namba N, Novack D, Woodring J, Pacifici R 2000 Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-{alpha}. J Clin Invest 106:1229–1237[Medline]
  7. Baldock PA, Sainsbury A, Couzens M, Enriquez RF, Thomas GP, Gardiner EM, Herzog H 2002 Hypothalamic Y2 receptors regulate bone formation. J Clin Invest 109:915–921[CrossRef][Medline]
  8. Bunyan J, Murrell EA, Shah PP 1976 The induction of obesity in rodents by means of monosodium glutamate. Br J Nutr 35:25–39[CrossRef][Medline]
  9. Parfitt AM, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR 1987 Bone histomorphometry: standardization of nomenclature, symbols, and units. Report of the ASBMR Histomorphometry Committee. J Bone Miner Res 6:595–610
  10. Ausubel FM 1995 Current protocols in molecular biology. Edison, NJ: John Wiley & Sons
  11. Franklin KBJ, Paxinos G 1997 The mouse brain in stereotaxic coordinates. San Diego: Academic Press
  12. Chappard D, Palle S, Alexandre C, Vico L, Riffat G 1987 Bone embedding in pure methyl methacrylate at low temperature preserves enzyme activities. Acta Histochem 81:183–190[Medline]
  13. Baron R, Vignery A, Neff L, Silverglate A, Maria AS 1983 Processing of undecalcified bone specimens for bone histomorphometry. In: RR R, ed. Bone histomorphometry: techniques and interpretation. Boca Raton, FL: CRC Press; 13–35
  14. Elmquist JK, Elias CF, Saper CB 1999 From lesions to leptin: hypothalamic control of food intake and body weight. Neuron 22:221–232[CrossRef][Medline]
  15. Ahima RS, Saper CB, Flier JS, Elmquist JK 2000 Leptin regulation of neuroendocrine systems. Front Neuroendocrinol 21:263–307[CrossRef][Medline]
  16. Wagner CK, Pfau JL, De Vries GJ, Merchenthaler IJ 2001 Sex differences in progesterone receptor immunoreactivity in neonatal mouse brain depend on estrogen receptor {alpha} expression. J Neurobiol 47:176–182[CrossRef][Medline]
  17. Francis K, Meddle SL, Bishop VR, Russell JA 2002 Progesterone receptor expression in the pregnant and parturient rat hypothalamus and brainstem. Brain Res 927:18–26[CrossRef][Medline]
  18. Hughes DE, Dai A, Tiffee JC, Li HH, Mundy GR, Boyce BF 1996 Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-ß. Nat Med 2:1132–1136[CrossRef][Medline]
  19. Manolagas SC 2000 Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 21:115–137[Abstract/Free Full Text]
  20. Swaminathan R 2001 Biochemical markers of bone turnover. Clin Chim Acta 313:95–105[CrossRef][Medline]
  21. Bergen HT, Mizuno TM, Taylor J, Mobbs CV 1998 Hyperphagia and weight gain after gold-thioglucose: relation to hypothalamic neuropeptide Y and proopiomelanocortin. Endocrinology 139:4483–4488[Abstract/Free Full Text]
  22. 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 5:15043–15048
  23. Ducy P, Amling M, Takeda S, Priemel M, Schilling AF, Beil FT, Shen J, Vinson C, Rueger JM, Karsenty G 2000 Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell 100:197–207[CrossRef][Medline]
  24. Elmquist JK, Maratos-Flier E, Saper CV, Flier JS 1998 Unraveling the central nervous system pathways underlying responses to leptin. Nat Neurosci 6:445–450
  25. Schwartz MW, Woods SC, Porte Jr D, Seeley RJ, Baskin DG 2000 Central nervous system control of food intake. Nature 404:661–671[Medline]
  26. Catzeflis C, Pierroz DD, Rohner-Jeanrenaud F, Rivier JE, Sizonenko PC, Aubert ML 1993 Neuropeptide Y administered chronically into the lateral ventricle profoundly inhibits both the gonadotropic and the somatotropic axis in intact adult female rats. Endocrinology 132:224–234[Abstract/Free Full Text]
  27. Sainsbury A, Cusin I, Rohner-Jeanrenaud F, Jeanrenaud B 1997 Adrenalectomy prevents the obesity syndrome produced by chronic central neuropeptide Y infusion in normal rats. Diabetes 46:209–214[Abstract]
  28. Baran K, Preston E, Wilks D, Cooney GJ, Kraegen EW, Sainsbury A 2002 Chronic central melanocortin-4 receptor antagonism and central neuropeptide-Y infusion in rats produce increased adiposity by divergent pathways. Diabetes 51:152–158[Abstract/Free Full Text]



This article has been cited by other articles:


Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
E. F. Gluck, N. Stephens, and S. J. Swoap
Peripheral ghrelin deepens torpor bouts in mice through the arcuate nucleus neuropeptide Y signaling pathway
Am J Physiol Regulatory Integrative Comp Physiol, November 1, 2006; 291(5): R1303 - R1309.
[Abstract] [Full Text] [PDF]

Home page
 IBMS BoneKEyHome page
G. Karsenty
New Examples of a Central Control of Bone Mass
IBMS BoneKEy, November 1, 2005; 2(11): 34 - 35.
[Full Text] [PDF]

Home page
 Arch Intern MedHome page
L. Fontana, J. L. Shew, J. O. Holloszy, and D. T. Villareal
Low Bone Mass in Subjects on a Long-term Raw Vegetarian Diet
Arch Intern Med, March 28, 2005; 165(6): 684 - 689.
[Abstract] [Full Text] [PDF]

Home page
 Proc. Natl. Acad. Sci. USAHome page
F. Elefteriou, S. Takeda, K. Ebihara, J. Magre, N. Patano, C. Ae Kim, Y. Ogawa, X. Liu, S. M. Ware, W. J. Craigen, et al.
Serum leptin level is a regulator of bone mass
PNAS, March 2, 2004; 101(9): 3258 - 3263.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Copyright Permission
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Elefteriou, F.
Right arrow Articles by Karsenty, G.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Elefteriou, F.
Right arrow Articles by Karsenty, G.

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