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Endocrinology Vol. 139, No. 11 4483-4488
Copyright © 1998 by The Endocrine Society

ARTICLES

Hyperphagia and Weight Gain after Gold-Thioglucose: Relation to Hypothalamic Neuropeptide Y and Proopiomelanocortin1

Hugo T. Bergen, Tooru M. Mizuno, Jason Taylor and Charles V. Mobbs

Department of Human Anatomy and Cell Science, University of Manitoba (H.T.B., J.T.), Winnipeg, Manitoba, Canada R3E 0W3; and the Fishberg Center in Neurobiology, Mt. Sinai School of Medicine (T.M., C.V.M.), New York, New York 10029

Address all correspondence and requests for reprints to: Dr. Hugo T. Bergen, Department of Human Anatomy and Cell Science, University of Manitoba, 730 William Avenue, Winnipeg, Manitoba, Canada R3E 0W3. E-mail: hbergen{at}cc.umanitoba.ca


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Genetic obesity is associated with increased neuropeptide Y (NPY) messenger RNA (mRNA) and decreased POMC mRNA in the hypothalamus of ob/ob and db/db mice, or impaired sensitivity to {alpha}MSH (derived from POMC) in the yellow agouti mouse. Acquired obesity can be produced by chemically lesioning the hypothalamus with either monosodium glutamate (MSG) in neonates or gold thioglucose (GTG) in adult mice. The present study examined whether elevated NPY mRNA and/or decreased POMC mRNA in the hypothalamus are associated with obesity due to hypothalamic lesions. GTG injection into adult mice produced a profound obese phenotype, including hyperphagia, increased body weight, and increased leptin mRNA and peptide, in association with reduced hypothalamic NPY mRNA and POMC mRNA. MSG treatment produced virtual elimination of NPY mRNA in the arcuate nucleus and a reduction of hypothalamic POMC mRNA, and led to elevated leptin. MSG pretreatment did not attenuate GTG-induced hyperphagia and obese phenotype. These results do not support a role for NPY-synthesizing neurons in the arcuate nucleus in mediating hypothalamic acquired obesity, but are consistent with the hypothesis that decreased activity of hypothalamic neurons synthesizing POMC play a role in mediating hypothalamic obesity.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
ELEVATED synthesis of neuropeptide Y (NPY) in the arcuate nucleus has been proposed to play an important role in mediating the obese phenotype in genetically obese animals (1, 2). This hypothesis is widely viewed as credible because 1) experimental elevation of hypothalamic NPY can induce obesity (1); 2) in some forms of genetic obesity, NPY messenger RNA (mRNA) in the arcuate nucleus is elevated (3, 4, 5, 6); 3) leptin inhibits NPY mRNA in the arcuate nucleus (3, 7); and 4) obesity is attenuated in leptin-deficient ob/ob mice that lack NPY (8). On the other hand, reduced POMC activity is also implicated in obesity, as 1) obesity in yellow agouti mice is associated with interference in response to {alpha}MSH, which is derived from POMC (9, 10, 11, 12, 13); 2) genetic deletion of an {alpha}MSH receptor produces obesity (14); 3) central administration of {alpha}MSH or a melanocortin-4 receptor agonist inhibits food intake, whereas a melanocortin-4 receptor antagonist stimulates food intake (13, 15); and 4) the expression of hypothalamic POMC mRNA is reduced in genetically obese ob/ob and db/db mice and is stimulated by leptin (16, 17, 18).

Obesity can be acquired through several perturbations, including hypothalamic damage. Hypothalamic obesity has been reported in humans (19) as well as in other species, for example after neonatal administration of monosodium glutamate (MSG) (20) or treatment of adult mice with gold thioglucose (GTG) (21). An ip injection of GTG produces a lesion in the ventromedial hypothalamus whose localization is reproducible and which recapitulates the severe obese phenotype characteristic of lesions of the hypothalamic ventromedial nucleus produced by other means (e.g. an electrical current, an excitotoxin, or a tumor). Therefore, GTG has been used as a powerful tool to assess mechanisms of hypothalamic obesity (22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32). The hypothalamic lesion produced by GTG is dependent on insulin and the glucose moiety of the GTG molecule and is blocked by glucose uptake inhibitors, so GTG has been thought to primarily target the glucose-sensitive neurons of the hypothalamus (21, 33). This hypothesis was supported by the observation that mice with GTG lesions are insensitive to the satiety effects of glucose and the induction of feeding by 2-deoxyglucose, but are sensitive to the satiety effects of cholecystokinin (34). The present study examined whether increased hypothalamic NPY mRNA and/or decreased hypothalamic POMC mRNA are associated with GTG- or MSG-induced hypothalamic obesity.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals and tissues
Adult mice (C57BL/6J) were bred in the institutional animal facility. On postnatal day 4, pups were given a single injection of either saline (Sal) or MSG (4 mg/g BW). The mice were weaned at 3 weeks, and 2 months later were weighed and then injected ip with either GTG (0.8 mg/g BW) or Sal for a total of four groups (Sal/Sal, Sal/GTG, MSG/Sal, and MSG/GTG). Groups were balanced to have approximately equal distributions of gender (Sal/Sal, four males and five females; Sal/GTG, three males and five females; MSG/Sal, three males and four females; MSG/GTG, three males and seven females; numbers reflect final distributions in each group after exclusion of GTG-injected mice that died, showed persistent toxic effects, or failed to exhibit GTG-induced lesions or obesity); in the final data analysis there was no effect of gender, so the two genders were pooled for each group. Before injection of GTG, the initial body weights of the four groups were (mean ± SEM, in grams): Sal/Sal, 21.9 ± 1.4; Sal/GTG, 22.4 ± 1.4; MSG/Sal, 22.7 ± 1.4; and MSG/GTG, 20.8 ± 1. There was no difference between the groups in initial (pre-GTG) body weight. After injection of GTG or saline, the mice were housed individually, and daily food intake was measured. Mice that died or showed toxic effects in response to GTG (for example, body weight loss that persisted for more than 4 days after the GTG injection; n = 9) and mice in which GTG failed to produce an observable lesion (correlated with development of obesity) were excluded from the study. Mice were weighed at regular intervals and were killed 2 weeks after GTG (or saline) injection. Mice were killed by carbon dioxide asphyxiation and decapitated, and their brains were rapidly removed and frozen with powdered dry ice. The brains were kept frozen at -70 C until sectioned (10 µm) on a cryostat.

In situ hybridization
NPY in situ hybridization was carried out as described previously (35), and POMC in situ hybridization used the same methods, but with a probe generated using PCR and the following oligonucleotides: N-terminal primer, 5'-CCTGTGAAGGTGTACCCCAATGTC-3'; and C-terminal primer, 5'-CACGTTCTTGATGATGGCGTTC-3'. Frozen coronal sections (10 µm thick) through the mouse hypothalamus were thaw-mounted onto subbed slides, fixed in 4% paraformaldehyde in 0.1 M phosphate buffer (pH 7.0) containing 0.03% diethylpyrocarbonate, dehydrated, and stored at -20 C until use. Representative sections through the hypothalamus were stained with cresyl violet, and sorting of the slides on the basis of histology was carried out to ensure that sections were matched for anterior-posterior level. Sections were prehybridized in 2 x SSC (standard saline citrate), 5 mM EDTA, 2.5 x Denhardt’s solution, 5 mM dithiothreitol, 100 mg/ml herring sperm DNA, 100 mg/ml yeast transfer RNA, 5 mg/ml single stranded calf thymus DNA, and 50% deionized formamide for 2 h at 42 C. Hybridization was carried out in the same buffer containing 10% dextran sulfate and labeled probe (32P; 2 x 106 dpm/20 µl·section) at 42 C overnight. Sections (two sections per matched anterior-posterior level) were washed twice in 1 x SSC for 15 min each time and in 0.1 x SSC overnight at room temperature, followed by a final wash in 0.1 x SSC for 1 h at 55 C. Slides were dehydrated, air-dried, and apposed to autoradiography film. After several exposures of the slides to film (2, 4, and 7 days), signal was quantified on an MCID system (Ontario, Canada). To quantify, a lens was used to magnify and capture the image of each brain, keeping magnification and lighting identical for the entire study. An area of constant size was placed over the region in the hypothalamus exhibiting signal, and the optical density of this region, subtracting out background, was determined by the MCID system. This corrected optical density was presumed to reflect the NPY or POMC mRNA. Cresyl violet-stained sections were also used to confirm the presence or absence of lesions under blinded conditions.

Northern blot analysis
Adipose tissue from the gonadal fat pad was removed, frozen with dry ice, and kept frozen at -70 C until Northern blot analysis was performed according to previously described protocols (36), using the MCID system to quantify films. Serum was retained for measurement of leptin using a commercially available RIA kit (Linco Research, Inc., St. Charles, MO).

Statistical analysis
Two-way ANOVA followed by Newman-Keuls post-hoc test were used to determine significant differences between groups. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
GTG lesion decreases hypothalamic NPY mRNA and POMC mRNA and leads to increased feeding, body weight, and leptin mRNA and peptide
In mice injected with saline as neonates and with GTG as adults, a hypothalamic lesion was observed that extended from the lateral arcuate nucleus through the ventrolateral aspect of the ventromedial nucleus (Fig. 1BGo). The GTG lesion overlapped with the medial aspect of the distribution of both NPY and POMC mRNA (Fig. 2Go, A and B), leading to a decrease in both mRNAs (P < 0.05; Fig. 3Go, A and B, Sal/GTG vs. Sal/Sal). GTG had no detectable effect on NPY mRNA in dorsomedial nucleus, cortex, or other parts of the forebrain. GTG-injected mice became hyperphagic and exhibited a significant increase in body weight gain over the 2-week period following injection of GTG (P < 0.05; Fig. 3Go, C and D; Sal/GTG vs. Sal/Sal), in association with significant increases in circulating levels of leptin and leptin mRNA (P < 0.05; Figs. 4Go and 5Go).



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  		Figure 1. Photomicrographs of sections through the ventromedial hypothalamus demonstrating the lesions produced by GTG (B), MSG (C), and MSG and GTG (D) injected into the same mouse. A is taken from a mouse injected with saline neonatally and as an adult. MSG treatment results in an arcuate nucleus that appears sparsely populated with cells (compared with controls), whereas GTG produces a lesion in the ventromedial hypothalamus together with scar tissue that appears to encroach on the most dorsolateral aspect of the arcuate nucleus. In each of the photomicrographs, the third ventricle is seen along the left edge. Scale bar = 100 µm.

 


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  		Figure 2. In situ hybridization of NPY mRNA (A) and POMC mRNA (B) in sections through the ventromedial hypothalamus exposed to film, demonstrating the effects of GTG alone (Sal/GTG), MSG alone (MSG/Sal), and MSG followed by GTG injected into the same mouse (MSG/GTG). The first column (Sal/Sal) is taken from a mouse injected with saline neonatally and as an adult. The third ventricle is at the center of each image, flanked by the symmetric bilateral arcuate and ventromedial nuclei; the top of each image is just above the top of the third ventricle, and the lateral aspect of each image indicates the lateral extent of the brain section at this level.

 


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  		Figure 3. Effects of GTG alone (Sal/GTG), MSG alone (MSG/Sal), or MSG followed by GTG injected into the same mouse (MSG/GTG), compared with controls injected with saline neonatally and saline as adults (Sal/Sal), on hypothalamic NPY mRNA (A), hypothalamic POMC mRNA (B), and total food intake per mouse on days 10–14 after GTG (or saline) injection (C). Body weight gain over the 14-day period following GTG (or saline) injection (D). Bars with different letters are significantly different (P < 0.05). Values are expressed as the mean ± SEM.

 


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  		Figure 4. Effects of GTG alone (Sal/GTG), MSG alone (MSG/Sal), or MSG followed by GTG injected into the same mouse (MSG/GTG), compared with controls injected with saline neonatally and saline as adults (Sal/Sal), on leptin mRNA, as demonstrated by Northern blot analysis (A). B indicates the 28S ribosomal RNA band in the same sample, as visualized by ethidium bromide stain. All samples contained equal amounts of RNA.

 


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  		Figure 5. Effects of GTG alone (Sal/GTG), MSG alone (MSG/Sal), or MSG followed by GTG injected into the same mouse (MSG/GTG), compared with controls injected with saline neonatally and saline as adults (Sal/Sal), on leptin serum peptide (A) and leptin mRNA (B). Bars with different letters are significantly different (P < 0.05). Values are expressed as the mean ± SEM.

 
MSG lesion decreases hypothalamic NPY mRNA and POMC mRNA and does not influence feeding or body weight, but leads to increased leptin mRNA and peptide
In mice injected with MSG as neonates and with saline as adults, a loss of neurons in the arcuate nucleus was observed, a lesion that was medial to the lesion produced by GTG (Fig. 1CGo). The MSG lesion entirely overlapped the NPY mRNA distribution (Fig. 2AGo), thus essentially eliminating NPY mRNA in the hypothalamus; the amount of NPY mRNA detected was not significantly greater than background (P > 0.05; Fig. 3AGo). MSG treatment had no detectable effect on NPY mRNA in cortex, dorsomedial nucleus, or other areas in the same section. The MSG lesion overlapped the medial aspect of the POMC mRNA distribution (Fig. 2BGo), decreasing POMC mRNA by 72% (P < 0.05; Fig. 3BGo). However, in contrast to NPY mRNA, POMC mRNA levels remained above background after the MSG lesion. In the mice injected with MSG as neonates and saline as adults (i.e. MSG/Sal), food intake and weight gain over a 2-week period were not significantly different from the food intake and weight gain of the saline-treated controls (Fig. 3Go, C and D; MSG/Sal vs. Sal/Sal). Similar to a previous report (37), MSG treatment alone, although not influencing body weight (see Materials and Methods), significantly increased circulating levels of leptin and leptin mRNA (P < 0.05; Figs. 4Go and 5Go).

Pretreatment with MSG does not prevent the GTG-induced increased feeding and body weight, and further increased leptin mRNA and peptide
In mice injected with MSG as neonates and subsequently injected with GTG, loss of neurons in the arcuate nucleus was observed together with a lesion in the ventromedial hypothalamus (Fig. 1DGo). As expected, the elimination of NPY mRNA in the arcuate by MSG was not altered by GTG, as NPY mRNA levels were not significantly above background after MSG treatment alone (Fig. 2AGo). In contrast, the combined lesions produced by MSG and GTG virtually eliminated both the medial and lateral aspects of the POMC mRNA field (Fig. 2BGo), leading to significantly lower POMC mRNA in mice injected with both MSG and GTG than in mice injected with either MSG or GTG alone (P < 0.05; MSG/GTG vs. MSG/Sal and MSG/GTG vs. Sal/GTG; Fig. 3BGo). Despite the elimination of NPY mRNA by treatment with MSG (Figs. 2AGo and 3AGo), the degree of hyperphagia and weight gain produced by the GTG lesion was not altered by pretreatment with MSG (P < 0.05; Fig. 3Go, C and D). The induction of obesity by GTG in MSG-treated mice was also associated with increased circulating levels of leptin and leptin mRNA levels (P < 0.05; Figs. 4Go and 5Go).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Corroborating previous reports (21), ip injection of GTG produced a profound obese phenotype, including hyperphagia and increased body weight concomitant with elevated leptin mRNA in adipose tissue and elevated plasma leptin (28). The induction of obesity by GTG lesions was associated with decreased hypothalamic NPY and POMC mRNAs. Neonatal injection of MSG also produced elevated leptin mRNA in adipose tissue and elevated plasma leptin peptide. The increases in leptin mRNA and peptide observed in this study are consistent with previous studies which have directly demonstrated that adipose stores increase in association with obesity induced by both GTG (38) and MSG (39, 40, 41). Also in agreement with previous studies, MSG-injected mice did not exhibit hyperphagia or increased body weight (41). MSG lesions virtually eliminated hypothalamic NPY mRNA and decreased hypothalamic POMC mRNA. Nevertheless, GTG injection resulted in similar hyperphagia, body weight gain, leptin mRNA, and leptin peptide regardless of whether the mice had been injected with MSG or saline as neonates. These data suggest that MSG treatment had no discernible effect on the obese phenotype produced by GTG.

Based on observations that elevated hypothalamic NPY is associated with several forms of obesity (1, 2, 3, 4, 5), the present study assessed the hypothesis that obesity due to hypothalamic lesions is associated with elevation of hypothalamic NPY mRNA. As the virtual elimination of NPY mRNA by MSG had little or no effect on the obese phenotype produced by GTG, and GTG alone decreased NPY mRNA in the arcuate nucleus, these data suggest that NPY does not play a role in mediating GTG-induced obesity. Similarly, NPY appears to play little role in the increase in leptin and leptin mRNA exhibited by mice treated with MSG alone. Nevertheless, it is possible that NPY outside the arcuate nucleus (i.e. NPY cells not destroyed by MSG) may mediate some effects of the GTG lesion. For example, it has been reported that agouti obese mice exhibit an elevation of NPY mRNA in the dorsomedial nucleus (6). However, this elevation of NPY mRNA in the dorsomedial nucleus only occurs after the development of obesity, and we have never observed an induction of NPY mRNA in the dorsomedial nucleus (or in any other part of the brain) in GTG- or MSG-treated mice. The hypothesis that NPY outside the arcuate nucleus mediates GTG-induced obesity could be tested by assessing whether NPY-deficient (knockout) mice develop obesity in response to GTG, but in any case most of the current data supporting a role for NPY in obesity are based on observations of NPY in the arcuate nucleus (1, 2, 3). Although NPY-deficient mice exhibit attenuated obesity in ob/ob mice (8), NPY-deficient mice have normal metabolic profiles and responses to leptin (42). Thus, the present data are most plausibly interpreted to indicate that, in contrast to the obesity of leptin-deficient mice (8), NPY plays little role in the profound obesity, including hyperphagia, exhibited by GTG-injected mice.

Based on observations that impaired synthesis of (16, 17, 18), processing of (43), and sensitivity to (9, 10, 11, 12, 13, 14) hypothalamic POMC products are associated with several forms of obesity, the present study assessed the hypothesis that obesity due to hypothalamic lesions is associated with decreased hypothalamic POMC mRNA. The results demonstrated that both MSG and GTG reduce hypothalamic POMC mRNA in association with obesity. Therefore, the current data are consistent with the hypothesis that products derived from hypothalamic POMC may well play a role in both MSG-induced obesity and the more profound obesity produced by GTG. However, it is important to note that MSG and GTG produce anatomically distinct lesions, and therefore may not destroy the same POMC-producing neurons. The center of the MSG-induced lesion is in the periventricular region of the arcuate nucleus, whereas the center of the GTG-induced lesion is lateral to this region, although the lesions may overlap in the lateral portion of the arcuate nucleus. POMC-producing neurons extend from the arcuate nucleus into an area well lateral to the arcuate nucleus, a distribution similar to (but somewhat medial to) that of the GTG lesion. Therefore, MSG appears to destroy the medial extent of the POMC field, GTG appears to destroy the lateral extent, and the two lesions may overlap to destroy the same neurons in the center of the POMC field. This hypothesis is supported by the observation that POMC mRNA is maximally reduced only in the presence of both lesions (in contrast to NPY, which is maximally reduced by MSG alone, with or without GTG). Therefore, as GTG produces a more profound obesity, including hyperphagia, this analysis suggests that the lateral POMC field (largely spared by MSG) may be more important in the control of body weight and feeding than the medial POMC field. Such a hypothesis is consistent with the observation that the lateral POMC field appears to be more sensitive to fasting and leptin (18).

As MSG and GTG both produce elevated leptin, suggesting leptin resistance, the present studies are consistent with the hypothesis that decreased activity of hypothalamic POMC neurons is associated with leptin resistance. Nevertheless, the POMC signaling system and the leptin system appear to be independent and additive (44). This suggests that although decreased POMC mRNA may lead to obesity and elevated leptin levels, the obesity is not caused by leptin resistance. Instead, as has been demonstrated in agouti mice, obesity may lead to leptin resistance secondary to elevated leptin. Decreased POMC mRNA in the hypothalamus is also associated with obesity produced by the canine distemper virus (45), obesity produced by deletion of the gene for the basic helix-loop-helix Nhlh2 transcription factor (46), and obesity due to leptin deficiency and resistance (16, 17, 18). A recent report has demonstrated that mutations in the POMC gene can cause profound obesity in humans (47). Together with those reports, the present study suggests that impairments in the synthesis, processing, or signaling of hypothalamic POMC products may be associated with many forms of both genetic and acquired obesity.


   Footnotes
 
1 This work was supported by grants from the Children’s Hospital Research Foundation (to H.T.B.) and the NIH (DK-50110; to C.V.M.). Back

Received April 1, 1998.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Dryden S, Frankish H, Wang Q, Williams G 1994 Neuropeptide Y and energy balance: one way ahead for the treatment of obesity? Eur J Clin Invest 24:293–308[Medline]
  2. Rohner-Jeanrenaud F, Cusin I, Sainsbury A, Zakrzewska KE, Jeanrenaud B 1996 The loop system between neuropeptide Y and leptin in normal and obese rodents. Horm Metab Res 28:642–648[Medline]
  3. Stephens TW, Basinski M, Bristow PK, Bue-Valleskey JM, Burgett SG, Craft L, Hale J, Hoffmann J, Hsiung HM, Kriauciunas A, Mackellar W, Rosteck PR, Jr, Schoner B, Smith D, Tinsley FC, Zhang X-Y, Heiman M 1995 The role of neuropeptide Y in the antiobesity action of the obese gene product. Nature 377:530–532[CrossRef][Medline]
  4. Wilding JP, Gilbey SG, Bailey CJ, Batt RA, Williams G, Ghatei MA, Bloom SR 1993 Increased neuropeptide-Y messenger ribonucleic acid (mRNA) and decreased neurotensin mRNA in the hypothalamus of the obese (ob/ob) mouse. Endocrinology 132:1939–1944[Abstract]
  5. Chua JSC, Brown AW, Kim J, Hennessey KL, Leibel RL, Hirsch J 1991 Food deprivation and hypothalamic neuropeptide gene expression: effects of strain background and the diabetes mutation. Mol Brain Res 11:291–299[Medline]
  6. Kesterson RA, Huszar D, Lynch CA, Simerly RB, Cone RD 1997 Induction of neuropeptide Y gene expression in the dorsal medial hypothalamic nucleus in two models of the agouti obesity syndrome. Mol Endocrinol 11:630–637[Abstract/Free Full Text]
  7. Schwartz MW, Seeley RJ, Campfield CA, Burn P, Baskin DG 1996 Identification of targets of leptin action in rat hypothalamus. J Clin Invest 98:1101–1106[Medline]
  8. Erickson JC, Hollopeter G, Palmiter RD 1996 Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y. Science 274:1704–1707[Abstract/Free Full Text]
  9. Bultman SJ, Michaud EJ, Woychik RP 1992 Molecular characterization of the mouse agouti locus. Cell 71:1195–1204[CrossRef][Medline]
  10. Miller MW, Duhl DM, Vrieling H, Cordes SP, Ollmann MM, Winkes BM, Barsh GS 1993 Cloning of the mouse agouti gene predicts a secreted protein ubiquitously expressed in mice carrying the lethal yellow mutation. Genes Dev 7:454–467[Abstract/Free Full Text]
  11. Klebig ML, Wilkinson JE, Geisler JG, Woychik RP 1995 Ectopic expression of the agouti gene in transgenic mice causes obesity, features of type II diabetes, and yellow fur. Proc Natl Acad Sci USA 92:4728–4732[Abstract/Free Full Text]
  12. Lu D, Willard D, Patel IR, Kadwell S, Overton L, Kost T, Luther M, Chen W, Woychik RP, Wilkison WO, Cone RD 1994 Agouti protein is an antagonist of the melanocyte-stimulating-hormone receptor. Nature 371:799–802[CrossRef][Medline]
  13. Fan W, Boston BA, Kesterson RA, Hruby VJ, Cone RD 1997 Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385:165–168[CrossRef][Medline]
  14. Huszar D, Lynch CA, Fairchild-Huntress V, Dunmore JH, Fang Q, Berkemeier LR, Gu W, Kesterson RA, Boston BA, Cone RD, Smith FJ, Campfield LA, Burn P, Lee F 1997 Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88:131–141[CrossRef][Medline]
  15. Tsujii S, Bray GA 1989 Acetylation alters the feeding response to MSH and ß-endorphin. Brain Res Bull 23:165–169[CrossRef][Medline]
  16. Thornton JE, Cheung CC, Clifton DK, Steiner RA 1997 Regulation of hypothalamic proopiomelanocortin mRNA by leptin in ob/ob mice. Endocrinology 138:5063–5066[Abstract/Free Full Text]
  17. Schwartz MW, Seeley RJ, Woods SC, Weigle DS, Campfield LA, Burn P, Baskin DG 1997 Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes 46:2119–2123[Abstract]
  18. Mizuno TM, Kleopoulos SP, Bergen H, Roberts JL, Priest CA, Mobbs CV 1998 Hypothalamic pro-opiomelanocortin mRNA is reduced by fasting and in ob/ob and db/db mice, but is stimulated by leptin. Diabetes 47:294–297[Abstract]
  19. Bray GA 1984 Syndromes of hypothalamic obesity in man. Pediatr Ann 13:525–536[Medline]
  20. Meister B, Ceccatelli S, Hokfelt T, Anden N-E, Anden M, Theodorsson E 1989 Neurotransmitters, neuropeptides and binding sites in the rat mediobasal hypothalamus: effects of monosodium glutamate. Exp Brain Res 76:343–368[Medline]
  21. Debons AF, Krimsky I, Maayan ML, Fani K, Jemenez FA 1977 Gold thioglucose obesity syndrome. Fed Proc 36:143–147[Medline]
  22. Coscina DV, McArthur RA, Stancer HC, Godse DD 1978 Association of altered brain norephinephrine and serotonin with the obesity induced by goldthioglucose in mice. Pharmacol Biochem Behav 9:123–128[CrossRef][Medline]
  23. Debons AF, Siclari E, Das KC, Fuhr B 1982 Gold thioglucose-induced hypothalamic damage, hyperphagia, and obesity: dependence on the adrenal gland. Endocrinology 110:2024–2029[Abstract]
  24. Houseknecht KL, Mantzoros CS, Kuliawat R, Hadro E, Flier JS, Kahn BB 1996 Evidence for leptin binding to proteins in serum of rodents and humans: modulation with obesity. Diabetes 45:1638–1643[Abstract]
  25. Heydrick SJ, Gautier N, Olichon-Berthe C, Van Obberghen E, Le Marchand-Brustel Y 1995 Early alteration of insulin stimulation of PI 3-kinase in muscle and adipocyte from gold thioglucose obese mice. Am J Physiol 268:E604–E612
  26. Lorden JF, Dawson Jr R, Callahan M 1979 Effects of goldthioglucose lesions on central catecholamine levels in the mouse. Pharmacol Biochem Behav 10:165–169[CrossRef][Medline]
  27. Machado UF, Shimizu I, Saito M 1994 Reduced content and preserved translocation of glucose transporter (GLUT 4) in white adipose tissue of obese mice. Physiol Behav 55:621–625[CrossRef][Medline]
  28. Maffei M, Fei H, Lee GH, Dani C, Leroy P, Zhang Y, Proenca R, Negrel R, Ailhaud G, Friedman JM 1995 Increased expression in adipocytes of ob RNA in mice with lesions of the hypothalamus and with mutations at the db locus. Proc Natl Acad Sci USA 92:6957–6960[Abstract/Free Full Text]
  29. Marks JL, Waite K, Cameron-Smith D, Blair SC, Cooney GJ 1996 Effects of gold thioglucose on neuropeptide Y messenger RNA levels in the mouse hypothalamus. Am J Physiol 270:R1208–R1214
  30. Pace C, Delmo C, Lee R 1989 Altered electrical responses of B-cells after goldthioglucose-induced lesions in the ventromedial hypothalamus. Res Commun Chem Pathol Pharmacol 65:401–404[Medline]
  31. Saito M, Bray GA 1983 Diurnal rhythm for corticosterone in obese (ob/ob), diabetes (db/db) and gold-thioglucose-induced obesity in mice. Endocrinology 113:2181–2185[Abstract]
  32. Silva E, Hernandez L 1989 Goldthioglucose causes brain norepinephrine and serotonin depletion correlated with increased body weight. Brain Res 490:192–195[CrossRef][Medline]
  33. Brown DF, Viles JM 1982 Systemic phlorizin prevents gold thioglucose necrosis in the ventromedial hypothalamus. Brain Res Bull 8:347–351[CrossRef][Medline]
  34. Bergen HT, Monkman N, Mobbs CV 1996 Injection with gold thioglucose impairs sensitivity to glucose: evidence that glucose-responsive neurons are important for long-term regulation of body weight. Brain Res 734:332–336[CrossRef][Medline]
  35. Bergen HT, Mobbs CV 1996 Ventromedial hypothalamic lesions produced by gold thioglucose do not impair induction of NPY mRNA in the arcuate nucleus by fasting. Brain Res 707:266–271[CrossRef][Medline]
  36. Mizuno TM, Bergen H, Funabashi T, Kleopoulos SP, Zhong YG, Bauman WA, Mobbs CV 1996 Obese gene expression: reduction by fasting and stimulation by insulin and glucose in lean mice, and persistent elevation in acquired (diet-induced) and genetic (yellow agouti) obesity. Proc Natl Acad Sci USA 93:3434–3438[Abstract/Free Full Text]
  37. Frederich RC, Löllmann B, Hamann A, Napolitano-Rosen A, Kahn BB, Lowell BB, Flier JS 1995 Expression of ob mRNA and its encoded protein in rodents: Impact of nutrition and obesity. J Clin Invest 96:1658–1663
  38. De Laey P 1975 Hypothalamic and nutritional obesities in mice. A comparative study of growth and body composition. Arch Int Pharmacodyn Ther 216:288–314[Medline]
  39. Cameron DP, Cutbush L, Opat F 1978 Effects of monosodium glutamate-induced obesity in mice on carbohydrate metabolism in insulin secretion. Clin Exp Pharmacol Physiol 5:41–51[Medline]
  40. Zhang WM, Kuchar S, Mozes S 1994 Body fat and RNA content of the VMH cells in rats neonatally treated with monosodium glutamate. Brain Res Bull 35:383–385[CrossRef][Medline]
  41. 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]
  42. Erickson JC, Clegg KE, Palmiter RD 1996 Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y. Nature 381:415–418[CrossRef][Medline]
  43. Cool DR, Normant E, Shen F, Chen HC, Pannell L, Zhang Y, Loh YP 1997 Carboxypeptidase E is a regulated secretory pathway sorting receptor: genetic obliteration leads to endocrine disorders in Cpe(fat) mice. Cell 88:73–83[CrossRef][Medline]
  44. Boston BA, Blaydon KM, Varnerin J, Cone RD 1997 Independent and additive effects of central POMC and leptin pathways on murine obesity. Science 278:1641–1644[Abstract/Free Full Text]
  45. Nagashima K, Zabriskie JB, Lyons MJ 1992 Virus-induced obesity in mice: association with a hypothalamic lesion. J Neuropathol Exp Neurol 51:101–109[Medline]
  46. Good DJ, Porter FD, Mahon KA, Parlow AF, Westphal H, Kirsch IR 1997 Hypogonadism and obesity in mice with a targeted deletion of the Nhlh2 gene. Nat Genet 15:397–401[CrossRef][Medline]
  47. Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A 1998 Severe early-onset obesity, adrenal insufficiency, and red hair pigmentation caused by POMC mutations in humans. Nat Genet 19:155–157[CrossRef][Medline]



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