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School of Biological Sciences, University of Manchester, Manchester, United Kingdom M13 9PT
Address all correspondence and requests for reprints to: Dr. Simon M. Luckman, University of Manchester School of Biological Sciences, 1.124 Stopford Building, Oxford Road, Manchester, United Kingdom M13 9PT. E-mail: simon.luckman{at}man.ac.uk.
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Abstract |
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Introduction |
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NMU is involved in the central control of feeding (12). Intracerebroventricular (icv) administration of NMU results in a decrease in overnight food intake and time spent feeding, concomitant with transient increases in core body temperature, gross motor activity, and oxygen consumption (12, 13, 14). Central injection of anti-NMU IgG increases dark phase feeding, further suggesting that NMU is a potent endogenous anorexic peptide (13). Fasting rats for 48 h is reported to result in a significant decrease in NMU mRNA in the mediobasal hypothalamus (-33 ± 5%) relative to that in controls (12). In leptin-deficient ob/ob mice, levels of NMU mRNA in the suprachiasmatic nucleus (SCN) are reduced relative to those in lean controls (12).
NMU also affects the release of stress modulators, ACTH and corticosterone, from pituitary and adrenal glands, suggesting a role in the regulation of the hypothalamo-pituitary-adrenal axis (15). NMU has been linked to the thyroid axis, with reports that NMU content increases in the anterior pituitary after the administration of TRH (16). In addition, NMU increases arterial blood pressure (4) and modifies ion transport in the intestinal tract (17). The localization of NMU by RIAs to the nucleus accumbens and substantia nigra suggests an additional role for NMU in the modulation of dopaminergic action (6).
In situ analysis reveals a discrete pattern of NMU mRNA expression within the mediobasal aspect of the hypothalamus (lateral arcuate nucleus and median eminence) and caudal brain stem [nucleus of the solitary tract (NTS), area postrema, dorsal motor nucleus of the vagus nerve, and inferior olive] (12). Immunoreactive (-ir) cell bodies are reported exclusively in the arcuate nucleus rostrocaudally (8, 9), and NMU-ir fibers are widely distributed and are localized to the nucleus accumbens, hypothalamic regions (paraventricular nucleus and supraoptic nucleus), medial thalamus, and brain stem, with dense terminal fields primarily in the NTS and parabrachial nucleus (8, 9)
Biologically active NMUs are the endogenous ligands for two G protein-coupled receptors, FM-3 (hereafter referred to as NMU1R) and FM-4 (NMU2R) (3, 11, 12, 13, 18, 19, 20, 21). NMU1R is expressed in numerous peripheral tissues, with little or no expression in the rat or human central nervous system (19, 21). In contrast, the highest levels of NMU2R transcript are located within the central nervous system and uterus. In the rat, NMU2R message has been detected by RT-PCR in the hypothalamus, spinal cord, and brain stem (18), and by in situ hybridization, transcript has been discretely localized in the paraventricular nucleus of the hypothalamus, along the third wall of the ventricle and the CA1 region of the hippocampus (12).
The aim of this study was to investigate further the central action of NMU on energy homeostasis. Having confirmed the acute effect of icv NMU administration on feeding and core body temperature, we determined, by c-Fos immunohistochemistry, the pattern of neuron activation after NMU administration. Key objectives were to reevaluate the distribution of NMU mRNA in the brain and pituitary gland and to quantify changes in transcript levels in the 48-h fasted rat and in a chronic model of obesity, the Zucker rat.
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Materials and Methods |
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Effect of NMU on food intake and body temperature
In the first experiment, vehicle (2 µl saline; n = 5) or rat NMU (4 nmol in 2 µl; n = 6; Bachem, Saffron Walden, UK) was injected into 24-h fasted rats. This dose was chosen after consultation of the literature and following our own preliminary experiments. For both free-feeding and fasted rats, dose-related physiological effects were obtained in response to 2 and 4 nmol NMU (results not shown). Immediately after injections, animals were presented with a preweighed amount of chow; food consumption was measured at 1, 2, 6, and 24 h, and body weight was determined at 6 and 24 h. In the second experiment, normally fed, satiated rats were injected icv with either vehicle (2 µl saline; n = 5) or rat NMU (4 nmol in 2 µl; n = 6). Food consumption and body weight were measured at 6 and 24 h. In both experiments core body temperature was monitored throughout the experimental period. All data are presented as the mean ± SEM. Food intake and body weight analyses were carried out using nonparametric Mann-Whitney U tests. Body temperatures were plotted as the mean change from the time of injection (time zero) and were analyzed by calculating the integrated temperature response for a defined period after injection [area under the curve (AUC); degrees centigrade per hour] for each animal by the trapezoidal method. Average AUC values were then determined for each treatment group.
Immunohistochemistry
Ninety minutes after icv administration of vehicle (n = 6) or 4 mol rat NMU (n = 6), deeply anesthetized rats were perfused transcardially with heparinized isotonic saline, followed by 4% paraformaldehyde in 0.1 M phosphate buffer (PB). Brains were removed, cryoprotected in 30% sucrose, and frozen at -80 C. Coronal sections (30 µm) were cut with a sledge microtome through the forebrain (-0.46 mm to -3.90 mm to bregma), and caudal brain stem (-13.44 mm to -15.46 mm to bregma), according to the atlas of Paxinos and Watson (22) and were collected in PB. To deactivate endogenous peroxidase activity, sections were incubated with 20% methanol, 0.2% Triton X-100, and 1.5% hydrogen peroxide for 20 min. Sections were washed in PB, blocked for 60 min in PB, 0.3% Triton X-100, and 2% normal sheep serum (blocking solution) and then incubated overnight at 4 C in blocking solution containing a 1:1000 dilution of rabbit polyclonal anti-c-Fos antibody (Calbiochem, Nottingham, UK). Sections were brought to room temperature, washed in PB, and incubated for 2 h with a peroxidase-labeled antirabbit IgG antibody (Vector Laboratories, Inc., Peterborough, UK) diluted 1:200 in blocking solution. Nickel-intensified diaminobenzidine [DAB; 0.1 M sodium acetate (pH 6.0), 2.5% nickel sulfate, 0.2% glucose, 0.04% ammonium chloride, 0.25% DAB, and 
30 U/ml glucose oxidase] was used as the chromogen in the peroxidase reaction to produce a purple-black nuclear c-Fos reaction product. The reaction was followed using a microscope and was terminated by sequential washes in acetate buffer and PB.
To identify catecholaminergic neurons, a set of c-Fos-labeled sections was further processed for tyrosine hydroxylase immunostaining (TH). After c-Fos immunodetection, sections were washed in PB and incubated overnight at 4 C in a 1:32,000 dilution of a mouse monoclonal anti-TH antibody (mAB318, Chemicon, Harrow, UK) in PB, 0.3% Triton X-100, and 2% normal horse serum. Sections were washed and incubated sequentially with a 1:200 dilution of biotinylated antimouse secondary antibody, then with a streptavidin-biotinylated horseradish peroxidase complex (Amersham Pharmacia Biotech, Little Chalfont, UK), each for 2 h. After PB washes, DAB (0.05% DAB and 0.01% H2O2 in PB) was used to produce a brown cytoplasmic TH-immunoreactive product. The reaction was monitored as before and was terminated in PB. Sections were mounted onto gelatin-coated microscope slides and coverslipped.
Catecholamine cell groups were identified from published descriptions. Cell bodies of tuberoinfundibular A12 dopaminergic neurons are located throughout the rostrocaudal aspect of the arcuate nucleus (23). At rostral levels of the hypothalamus, dopaminergic cell bodies of the A14 cell group are seen in the periventricular region surrounding the floor of the third ventricle and extending into the paraventricular nucleus. Perikarya of the A13 group are located in the dorsal hypothalamus, with a dense cluster of cells in the zona incerta. In the brain stem, the C1 cell group consists of a column of adrenergic cells in the ventrolateral medulla, which extends caudally into the A1 noradrenergic cell group (24, 25). Similarly, the C2 adrenergic cell group is situated dorsally in the NTS, rostral to the A2 noradrenergic cell group.
In situ hybridization
Quantitative in situ hybridization was performed using a single-stranded NMU antisense oligonucleotide identical in sequence to a previously described NMU probe (12). The oligonucleotide was end labeled with [35S]deoxy-ATP (NEN Life Science Products, Hounslow, UK) and terminal deoxynucleotidyl transferase (Amersham Pharmacia Biotech) and was purified through a Sephadex G-50 column. Labeled NMU probe was successfully competed for by a 100-fold excess of cold probe oligonucleotide.
Coronal sections (15 µm) were cut from brain at the level of the arcuate nucleus (-1.78 mm to -3.70 mm to bregma) and caudal brain stem (-13.44 mm to -15.46 mm to bregma) (22) and through the pituitary gland. Before hybridization, sections were fixed for 30 min in cold 4% paraformaldehyde in 0.1 M PB (pH 7.4). Slides were rinsed twice in 0.1 M PBS (PB and 0.9% NaCl) and acetylated for 10 min in 0.25% acetic anhydride/0.1 M triethanolamine/0.9% NaCl. Sections were then taken through an increasing ethanol series, allowed to air-dry, and hybridized with 3 x 105 dpm/slide in buffer [10% dextran sulfate, 4x standard saline citrate (SSC; pH 7.0), 50% deionized formamide, 1x Denhardt’s solution, and 0.4 mg/ml salmon testes DNA], overnight in a moist chamber at 37 C. After hybridization, slides were dipped in 1x SSC at room temperature and then washed three times for 30 min each time in 1x SSC at 55 C, followed by a room temperature wash for more than 60 min in 1x SSC. Slides were then briefly washed in 300 mM ammonium acetate and 70% ethanol and air-dried. Slides were exposed to K5 nuclear emulsion (Ilford, Knutsford, UK) for autoradiography, and quantitation of signal was performed using Northern Eclipse (Empix Imaging, Inc., Mississauga, Canada), a computer-based imaging system.
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Results |
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). This was accompanied by a significant reduction in the change in body weight at 6 and 24 h (P < 0.01 for both time points; Fig. 1C). An increase in core body temperature was observed between 2 and 6 h, but failed to reach statistical significance (vehicle, 4.8 ± 1.2 C/h; NMU, 7.4 ± 1.6 C/h; P = 0.24, by unpaired t test on AUC; Fig. 1E). In satiated rats there was no significant difference in food intake (Fig. 1B) or change in body weight (Fig. 1D) over 6 and 24 h after NMU injection compared with vehicle-treated animals. Core body temperature was increased significantly in the NMU group between 2 and 4 h (vehicle, 2.2 ± 0.3 C/h; NMU, 3.2 ± 0.3 C/h; P = 0.03, by unpaired t test on AUC; Fig. 1F).
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and Fig. 2). Within the hypothalamus, increased c-Fos-ir was detected in the paraventricular nucleus, arcuate nucleus, dorsomedial nucleus, and lateral hypothalamic area. NMU also induced c-Fos expression in the central nucleus of the amygdala, NTS, and ventrolateral medulla. An apparent change in c-Fos-ir noted in the ventral ependymal layer of the third ventricle was not statistically significant.
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and Fig. 3). Conversely, 26 ± 5% of all activated c-Fos cells in the arcuate were dopaminergic (saline, 7 ± 2%; P = 0.009). Little c-Fos and TH colocalization was observed for two other forebrain populations: the A13 dopaminergic neurons located in the zona incerta and the A14 dopaminergic neurons of the periventricular nucleus (Table 2). In the paraventricular nucleus, c-Fos ir cells were present in both parvicellular and magnocellular regions (Fig. 2
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and Fig. 3). This expression overlap was most evident at the level of the area postrema, corresponding to the location of the A2 noradrenergic cell group. Few cells were double labeled in the NTS caudal to the area postrema. In the ventrolateral medulla, 27 ± 4% of TH-ir were immunoreactive for c-Fos after NMU administration compared with 0.2 ± 0.2% for saline controls (P = 0.002; Table 2 and Fig. 3). As with the NTS, double-labeled cells were observed primarily at the level of the area postrema corresponding to the A1/C1 overlap area. Rostral and caudal to the area postrema, the incidence of double-ir neurons in the ventrolateral medulla gradually decreased.
Expression of NMU
NMU transcript was detected in rat brain stem and pituitary gland. In caudal brain stem, significant and comparable levels were detected in the NTS (Fig. 4) and inferior olive (Table 3). Although not specifically analyzed, it appeared that gradients existed in the number of expressing cells (highest numbers at and rostral to area postrema) and the degree of expression (highest levels caudal to area postrema) in the NTS. Other brain stem regions expressing NMU included the dorsolateral surface of the brain stem (lateral to the spinal trigeminal nucleus) and, to a much lesser extent, the area postrema.
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). Within the NTS, small, nonsignificant decreases in NMU expression were observed in fasted rats relative to fed rats with respect to the level of NMU expression (P = 0.13) and the number of cells expressing NMU (P = 0.052). However, in the Zucker rat, a 81 ± 2.3% reduction in NMU expression was detected in the NTS of obese animals relative to lean. The number of cells expressing NMU did not differ between these two groups (P = 0.61). In the inferior olive, no differences were detected in the number of cells expressing NMU or the level of expression in either fasted or obese Zucker rats.
In the pituitary, a clustered pattern of NMU expression was observed in the pars tuberalis and pars distalis (Fig. 5). The signal in the pars tuberalis was seen clearly in coronal sections through the tuberoinfundibulum, abutting the ventral surface of the median eminence. Silver grains were not at a single plane of focus suggesting the organization of expressing cells into tubes or follicles. In the pars distalis, clusters of cells expressed NMU at relatively high levels against a background of low expressing cells. NMU transcript was also detected throughout the pars intermedia, but was absent in the pars nervosa and hypothalamic regions, including the median eminence and arcuate nucleus.
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). In the pars tuberalis, no significant difference was observed in NMU expression between fed and fasted rats. A significant reduction in expression (-72 ± 4.4%), however, was detected in obese Zucker rats relative to lean animals. In the pars distalis, a decrease in grain density was observed for both fasted rats (-68 ± 6.6%) and obese Zucker rats (-57 ± 13.1%). No differences in NMU expression were observed for either fasted or obese Zucker rats in the pars intermedia.
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Discussion |
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The distribution of NMU in the brain and pituitary suggests that it may have a variety of functions (8, 9, 12) and makes determination of the mechanism of NMU action on food intake and body weight complex. Howard and colleagues (12) have reported a change in the expression of NMU mRNA in ventromedial hypothalamic regions in what they term the lateral arcuate nucleus and median eminence of fasted rats. This coupled with the lack of conditioned taste aversion after central administration of the peptide (12) suggested that NMU is an endogenous regulator of food intake. However, careful examination of emulsion-dipped slides in our experiments revealed that NMU message is present not in either the arcuate nucleus or the median eminence, but, rather, in the pituitary pars tuberalis, a highly vascularized, multicellular tube of cells that surrounds the hypophyseal stalk and extends along the ventral surface of the median eminence (27, 28). The detection of NMU in the pars tuberalis is also seemingly at odds with immunocytochemistry that describes the presence of NMU in the arcuate nucleus (8, 9). However, although not discussed in the text of these previous papers, immunoreactive material is clearly visible on the ventral surface of the hypothalamus corresponding to the location of the pars tuberalis (8). Furthermore, another study that used a different antibody (29) failed to detect NMU-ir cell bodies in the arcuate nucleus. We have now confirmed our pattern of NMU mRNA expression with a second oligonucleotide probe to a different portion of the NMU transcript and with a 33P-labeled riboprobe (data not shown), suggesting that localization of NMU in the pars tuberalis and not in the arcuate nucleus is correct.
Here we demonstrate the regulation of NMU expression in both the pituitary and a separate brain region (the NTS) in two models of energy imbalance, the fasted rat and the Zucker rat. In the obese Zucker rat, which lacks a functional leptin receptor and is hyperphagic, NMU expression was significantly reduced in the brain stem NTS. Such a reduction in the expression of putative anorexic peptides in Zucker rats has been reported widely (30, 31, 32). The selectivity of this adaptation is exemplified by the lack of change in another population of the brain stem, NMU-expressing cells in the inferior olive. It is possible that the brain stem population of NMU-expressing cells is more important in mediating appetite effects. The NTS is involved in a number of autonomic and neuroendocrine functions. After the ingestion of a satiating meal, gastric distension and nutrients in the gut signal to the NTS, and this information is relayed to other brain stem and forebrain regions involved in the control of feeding (33).
The change in NMU expression in the pituitary may be secondary to endocrine adaptation in states of energy imbalance. Both fasted and Zucker rats show obvious changes in endocrine function, including decreased levels of GH and thyroid hormone (34). A photoperiodic function has been assigned to the pars tuberalis in some species, in that melatonin acts here to modulate the seasonal changes in pituitary PRL output (28). Interestingly, NMU is expressed in all regions of the rat pituitary except the pars nervosa, and its expression was down-regulated in both the pars tuberalis and the pars distalis of obese Zucker rats. Previous pituitary immunocytochemistry has localized NMU expression in a subset of pars distalis cells, including corticotropes and thyrotropes (5, 6, 8, 9). A decrease in pars distalis NMU expression was also noted in rats fasted for 48 h. The lack of modulation in the adjacent pars intermedia suggests selectivity in the response.
NMU administration induced prominent c-Fos expression in central areas, including those involved in the control of feeding behavior (paraventricular nucleus, arcuate nucleus, caudal brain stem, and central nucleus of the amygdala). The robust induction of c-Fos in the paraventricular nucleus may relate to the reported presence of dense NMU-ir fibers (8) and the NMU2R receptor message in this hypothalamic nucleus (12). This activation might include parvicellular neurons containing CRH, as these neurons are important in feeding and have recently been implicated in the locomotor activity induced by NMU (26). Interestingly, both NMU-ir fibers (8) and NMU2R mRNA are also found in cells of the ventral ependyma lining the third ventricle (12). Although icv injections commonly induce some c-Fos expression in the ependyma, in the present experiments more c-Fos immunoreactivity was detected in the ventral ependyma of the third ventricle of NMU-treated rats compared with vehicle-treated rats. Although this did not quite reach statistical significance, it warrants further investigation, because pituitary control of hypothalamic function has been previously suggested (28).
A prominent c-Fos induction was also observed in the arcuate nucleus, which is an important site for the integration of information concerning body weight regulation, notably by leptin-sensitive neuropeptide Y and proopiomelanocortin neurons (35). However, a significant population of the neurons activated in the dorsomedial and ventrolateral arcuate nucleus colocalized with tyrosine hydroxylase. Dorsomedial TH-ir neurons predominantly innervate the mid portion of the median eminence and are believed to inhibit PRL release from pituitary pars distalis lactotropes by the release of dopamine. Ventrolateral TH-ir neurons innervate lateral aspects of the median eminence, but the function of these cells is unknown, as they lack dihydroxyphenylalanine decarboxylase and do not synthesize dopamine (36). It is possible that if NMU from the pars tuberalis is capable of releasing PRL from the pituitary, the induction of c-Fos in dopaminergic neurons of the arcuate nucleus is secondary to negative feedback by this hormone (37). A link between NMU and dopaminergic function in other parts of the brain has been made previously (6). Alternatively, the c-Fos-ir noted here in the hypothalamus and amygdala may result indirectly from the activation of afferent cells. Catecholaminergic neurons in the NTS and ventrolateral medulla project to both the hypothalamus and central nucleus of the amygdala (38). By double immunocytochemistry, NMU was shown to induce c-Fos expression in 34% and 27% of TH-ir neurons in the NTS and ventrolateral medulla, respectively. For comparison, peripheral injection of another anorexic factor, cholecystokinin, which also activates the paraventricular nucleus and amygdala, results in c-Fos expression in 43% of catecholaminergic NTS neurons and in 46% of catecholaminergic ventrolateral medulla neurons (39).
Clearly, NMU is a potent anorexic peptide when administered centrally. The lack of a conditioned taste aversion by the same stimulus also suggests that it is of physiological relevance (12). Here we demonstrate that chronic imbalance of energy homeostasis, as seen in the obese Zucker rat, elicits regulation of NMU mRNA expression similar to that in fasted animals. The relative importance of different populations of NMU-expressing cells on food intake remains to be determined, although the population in the brain stem NTS may be well placed to mediate satiety signaling. We also demonstrate a response of NMU cells in certain regions of the pituitary, which may result from adaptation of endocrine systems to energy imbalance. Interestingly, in the mouse, NMU transcript is detected in the SCN of the hypothalamus (12), the site of the mammalian master circadian pacemaker. In the homozygote ob/ob mouse, which lacks circulating leptin, there is a reduction in the expression of NMU mRNA in the SCN (12). Although we did not detect NMU in the SCN of rats, regulation in the mouse SCN resembles our reported decrease in NMU mRNA in the obese Zucker’s pars tuberalis, another structure noted for its biological time keeping.
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Footnotes |
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Abbreviations: AUC, Area under the curve; DAB, diaminobenzidine; icv, intracerebroventricular; -ir, immunoreactivity, immunoreactive; NMU, neuromedin U; NTS, nucleus of the solitary tract; PB, phosphate buffer; SCN, suprachiasmatic nucleus; SSC, standard saline citrate; TH, tyrosine hydroxylase immunostaining.
Received January 31, 2002.
Accepted for publication June 11, 2002.
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-MSH are lower in obese relative to lean Zucker rats. Brain Res 862:11–16[CrossRef][Medline]
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or 
; n = 5) or 4 nmol NMU (
or 
; n = 6) was administered icv at 1000 h. Data shown are the mean ± SEM. Asterisks indicate significant differences between NMU and vehicle groups. **, P < 0.01, by Mann-Whitney U test.
