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Endocrine Unit, Faculty of Medicine, Imperial College, London W12 0NN, United Kingdom
Address all correspondence and requests for reprints to: Dr. Stephen Robert Bloom, Endocrine Unit, Faculty of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London W12 0NN, United Kingdom. E-mail: s.bloom{at}ic.ac.uk.
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Abstract |
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Introduction |
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NMU-LI and mRNA expression are abundant in the central nervous system (CNS), particularly in nuclei of the brainstem and hypothalamus (13, 15). Within the hypothalamus NMU-immunoreactive cell bodies and mRNA expression are restricted to the arcuate nucleus (Arc) and median eminence (13, 15). The paraventricular nucleus (PVN), ventromedial nucleus (VMN), dorsomedial nucleus (DMN), and Arc receive dense innervation by NMU-immunoreactive fibers (13). This pattern of neuronal location and projection is similar to that of other neural networks thought to regulate food intake and body weight (16). It has recently been shown that intracerebroventricular (icv) administration of NMU inhibits food intake and that hypothalamic NMU mRNA expression is reduced by fasting and in the leptin-deficient ob/ob mouse (15), suggesting that hypothalamic NMU may play a role in appetite inhibition. An aim of these studies was to further characterize the anorectic effect of NMU and its regulation by leptin.
Two G protein-coupled receptors, termed NMU1R and NMU2R, with a high affinity for NMU have been identified (15, 17, 18, 19, 20). NMU1R has a wide distribution in peripheral tissues, including the gastrointestinal tract and adrenal cortex, but is not found in the CNS (15). NMU2R is found in a number of peripheral tissues, but is also expressed in discrete CNS sites in rats and humans (15). Despite the fact that several hypothalamic nuclei, as described above, receive NMU projections, the only identified hypothalamic site of NMU2R expression is the PVN (15, 21). The PVN is important in the hypothalamic control of food intake (16). Many peptides known to alter food intake influence feeding most potently in this nucleus (22, 23, 24). It is also a key nucleus in the control of the hypothalamo-pituitary-adrenal (HPA) axis, being the site of CRH and arginine vasopressin (AVP) synthesis (25, 26).
Several observations suggest that NMU is linked to the HPA axis. In the pituitary, NMU-LI is found in the majority of corticotrophs (27, 28). Also, NMU may act directly on the adrenal gland. In vitro, NMU stimulates the synthesis of steroids by adrenal slices via a mechanism dependent upon the presence of medullary chromaffin cells (29). In vivo, NMU increases plasma corticosterone and the volume of the zona fasiculata following sc administration for 6 d in rats (30). It is not known whether NMU has a hypothalamic action on the release of CRH or AVP and, hence, the plasma concentrations of ACTH and adrenal steroids.
The current study aimed to investigate the effect of NMU on the HPA axis at the hypothalamic level in vivo by measuring the plasma ACTH and corticosterone responses to NMU after direct administration into the PVN. To explore the hypothalamic mechanism of action, the effect of NMU on the release of CRH and AVP from hypothalamic explants in vitro was investigated. Although the only confirmed hypothalamic site of NMU receptor expression is the PVN (15), NMU fibers project to several other hypothalamic nuclei (13). We aimed to localize the hypothalamic site of action of NMU on food intake by using microinjection into the hypothalamic sites that receive NMU-immunoreactive neuronal projections. We also investigated whether icv or intranuclear administration of NMU was associated with any changes in behavior other than feeding. Hypothalamic explants in vitro were used to examine the effect of leptin on NMU release. In this way we explored the site and mechanisms of the hypothalamic actions of NMU in the regulation of food intake, behavior, and the HPA axis.
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Materials and Methods |
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Materials
Full-length rat NMU (NMU-23) was custom synthesized (IAF Biochem, Québec, Canada) and used in all in vitro and in vivo experiments. Leptin was purchased from R\|[amp ]\|D Systems, Inc. (Minneapolis, MN). Reagents for basal hypothalamic explant experiments were supplied by BDH (Poole, UK).
Intracerebroventricular and intranuclear cannulation and injections
Animal surgical procedures and handling were carried out as previously described (24, 31). Animals were anesthetized by ip injection of a mixture of ketamine (60 mg/kg Ketalar, Parke-Davis, Pontypool, UK) and xylazine (12 mg/kg Rompun, Bayer Corp., Bury St. Edmunds, UK) and were placed in a Kopf stereotaxic frame (David Kopf, New York, NY). For icv cannulation, permanent 22-gauge stainless steel guide cannulas (Plastics One, Inc., Roanoke, VA) were placed into the third cerebral ventricle (0.8 mm posterior to the bregma on the midsagittal line 6.5 mm below the outer surface of the skull) (32). For intranuclear cannulation, animals were implanted with 26-gauge stainless steel guide cannulas (Plastics One, Inc.) projecting to the Arc, PVN, VMN, DMN, medial preoptic area (MPO), supraoptic nucleus (SON), anterior hypothalamic area (AHA), and lateral hypothalamic area (LHA) of the hypothalamus according to the coordinates of Paxinos and Watson (Fig. 1
) (32). These areas were chosen because they all receive innervation with NMU-immunoreactive fibers (13). All compounds were dissolved in 0.9% saline, and each study involved an injection of NMU or saline in a volume of 1 µl (intranuclear studies) or 5 µl (icv studies) over 1 min. NMU or saline was administered in the early light phase (0900–1000 h) by a 31-gauge (for intranuclear studies) or a 27-gauge (for icv studies) stainless steel injector placed in and projecting 1 mm below the tip of the cannulas. Correct icv cannula placement was confirmed by a positive dipsogenic response to angiotensin II (150 ng/rat). Only those animals with correct placement of cannulas were included in the data analysis. Correct intranuclear cannula placement was confirmed histologically at the end of the study period. After injection of 1 µl India ink, animals were decapitated, guide cannulas were removed, and brains were immediately frozen in liquid nitrogen and stored at -70 C. Brains were sliced on a cryostat (Bright, Huntingdon, UK) into 15-µm coronal sections and stained with cresyl violet. Sections were compared with the corresponding section from the rat brain atlas of Paxinos and Watson. The India ink remained localized at the injection site at the guide cannula tip without significant diffusion. Data from an animal were excluded if its injection site extended more than 0.2 mm outside the intended hypothalamic site of injection or if any India ink was detected in the cerebral ventricular system. Some 11.7 ± 2.4% (mean ± SEM) of cannulated animals were excluded due to cannula misplacement.
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. The tubes were placed on a shaking platform in a water bath maintained at 37 C. After an initial 2-h equilibration period, the hypothalami were incubated for 45 min in 600 µl aCSF (basal period) before being challenged with NMU (10, 100, or 1000 nM) or leptin (100 nM) in 600 µl aCSF. Finally, the viability of the tissue was verified by a 45-min exposure to aCSF containing 56 mM KCl. Isotonicity was maintained by substituting K+ for Na+. At the end of each period, the aCSF was removed and frozen at -20 C until measurement of CRH, AVP, and NMU by RIA. Our standard protocol for hypothalamic explants (33) is to use a peptide challenge at a concentration of approximately 100 times the IC50, i.e. 100 nM for NMU (34). We have found from previous experience that this concentration provides adequate stimulation, allowing for tissue penetration in hypothalamic explants. Hypothalamic explants were also challenged with 10-fold higher and lower concentrations of NMU (10 and 1000 nM), and the CRH and AVP responses were measured.
Investigation of the effect of icv NMU on food intake and behavior
After an overnight fast, rats (n = 13/group) were injected in the early light phase with saline or NMU (1 nmol) and immediately returned to their home cages containing a preweighed amount of rat chow. The dose of NMU chosen was based upon the lowest dose of NMU previously reported to inhibit food intake (15). Food was reweighed at 1, 2, 4, 8, and 24 h post injection using a GW 600 balance (ATP Instrumentations Ltd., Ashby-de-la-Zouche, UK) recording to the nearest 0.1 g. Rats (n = 6 from each treatment group) were observed continuously for 1 h post injection by observers blinded to the experimental treatment. Behavior was classified into seven different categories: feeding, drinking, grooming, rearing (defined as stationary with front paws elevated), head down (defined as stationary with all four paws on the cage bottom), locomotion (defined as moving around the cage, with all four paws moving), or sleeping [adapted from Fray et al. (35)]. Each rat was observed for 15 sec every 5 min during the test session. This 15-sec period was further divided into three 5-sec periods, and the behavior of the rat was scored in each section of the time period. Each rat had a total of 36 behaviors recorded per hour.
Investigation of the effect of NMU after microinjection into specific hypothalamic nuclei
A dose-response study was performed to investigate the effects of NMU on food intake in the paraventricular nucleus, as this nucleus has been shown to express the NMU2R (15, 21). After an overnight fast, rats (n = 10–11/group), cannulated into the PVN, were injected in the early light phase with saline or NMU (0.03, 0.1, 0.3, or 1.0 nmol). Food intake was measured as described above. To investigate the effect of NMU on food intake in other hypothalamic nuclei, separate groups of rats (n = 12–15 cannulated into each nucleus) received, in random order, saline or NMU (0.3 nmol) by intranuclear microinjection. The dose of NMU chosen was based on previous experience suggesting that the effective intranuclear dose of a peptide on food intake is generally between 1/3rd and 1/10th of the effective icv dose (24, 36, 37) and on a dose giving a robust effect in the PVN dose-response study. The study was of randomized cross-over design. Rats were injected in the early light phase (0900–1000 h) and immediately returned to their home cages, and food was reweighed as described above. The methods for localization of the neuropeptide effect by cannulation of multiple hypothalamic nuclei and injection of the neuropeptide of interest in a 1-µl volume of vehicle was established in previous studies (24, 36, 37). Final numbers of animals included in data analysis for each nucleus were: PVN, n = 13; LHA, n = 14; MPO, n = 12; DMN, n = 15; AHA, n = 15; SON, n = 14; Arc, n = 14; and VMN, n = 14.
Investigation of the effect of intra-PVN microinjection of NMU on behavior
After an overnight fast, a separate group of rats (n = 6/group), cannulated into the PVN, were injected in the early light phase with saline or NMU (0.3 nmol), and behavior was observed as described above.
Investigation of the effect of NMU on the HPA axis
A separate group of PVN cannulated rats were injected in the early light phase (0900–1000 h) with saline or NMU (0.3 nmol). Rats were killed by decapitation at 5, 10, and 20 min post injection (n = 9–10/group at each time point). A dose-response curve was performed at the 20-min point, as stimulation of the HPA axis was shown at this time after injection of NMU (0.3 nmol). An additional group of PVN-cannulated rats (n = 10–11/group) were injected in the early light phase (0900–1000 h) with saline or NMU (0.03, 0.1, 0.3, or 1.0 nmol). Rats were decapitated 20 min post injection. For both studies trunk blood was collected into plastic lithium heparin and EDTA tubes containing 0.6 mg aprotinin (Bayer Corp., Haywards Heath, UK). Plasma was separated by centrifugation, frozen, and stored at -70 C for subsequent ACTH measurement or -20 C for subsequent corticosterone measurement by RIA.
RIAs
ACTH was measured using a solid phase immunoradiometric assay (Euro-Diagnostica, Arnhem, The Netherlands). Plasma corticosterone was measured using a commercially available RIA kit (ICN Biomedicals, Inc., Costa Mesa, CA). CRH, AVP, and NMU were measured using RIAs developed in the department and described previously (10, 38, 39). Briefly, CRH-like immunoreactivity (CRH-LI) was measured using an antibody raised in a rabbit immunized with synthetic CRH-41 conjugated to BSA by glutaraldehyde and used at a final dilution of 1:380,000. [125I]Tyr-CRH was labeled by the Iodogen method and purified by reverse phase HPLC. The assay was performed in a total volume of 0.35 ml 0.06 M phosphate EDTA buffer (pH 7.2) containing 0.1% BSA and 0.2% Tween (1:10). AVP-LI was measured using an antibody raised in a rabbit immunized with Arg8-vasopressin conjugated to BSA by carbodiimide technique and used at a final dilution of 1:64,000. [125I]Arg8-vasopressin was labeled by the Iodogen method and purified by reverse phase HPLC. NMU-LI was measured using an antibody raised in a rabbit immunized with synthetic NMU-8 conjugated to BSA by glutaraldehyde and used at a final dilution of 1:56,000. 125I-Labeled NMU-8 tracer was prepared using the chloramine-T technique and was purified by reverse phase HPLC. The AVP and NMU assays were performed in a total volume of 0.7 ml 0.06 M phosphate EDTA buffer (pH 7.2) containing 0.3% BSA. All assays were incubated for 3–5 d at 4 C before separation of free and antibody-bound label by dextran-coated charcoal (6 mg/tube; BDH Norit, GSX), for NMU and AVP assays and sheep antirabbit antibody for CRH assay, followed by centrifugation at 2,500 rpm. Assay sensitivities were 2 fmol/tube for CRH, 0.5 fmol/tube for AVP, and 6 fmol/tube for NMU (at 95% confidence limits). The inter- and intraassay coefficients of variation were less than 10% for CRH and AVP and 13 and 9%, respectively, for NMU. The antibody used for AVP assay showed 50% cross-reactivity on a molar basis with lysine vasopressin. Other than this, the antibodies used did not cross-react with any known hypothalamic peptides.
Statistics
Paired t test was used for comparison of peptide release from hypothalamic explants in the basal and stimulated periods and between saline and NMU treatments in the intranuclear cross-over study. Unpaired t test was used for comparison of food intake between rats receiving saline or NMU (1 nnol, icv). One-way ANOVA with post hoc Tukey’s test was used for comparison of the effects on food intake and the HPA axis of intra-PVN administration of multiple doses of NMU to saline control. As behavioral observation data were not normally distributed, Kruskal-Wallis test was used for comparisons between treatment groups.
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Results |
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Investigation of the effect of NMU on food intake after microinjection into specific hypothalamic nuclei
Injection of NMU (0.03, 0.1, 0.3, or 1.0 nmol) into the hypothalamic PVN resulted in dose-dependent inhibition of food intake (Fig. 2A). The lowest effective dose was 0.1 nmol (0–1 h food intake, 6.4 ± 0.3 g; saline control, 8.2 ± 0.4; P < 0.05), with a robust effect at 0.3 nmol (0–1 h food intake, 5.8 ± 0.5 g; P < 0.01 vs. saline control).
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). Inhibition of 0–1 h food intake was also seen after intraarcuate NMU administration (76 ± 10.4% of control; P < 0.05; Fig. 2B). No immediate inhibition of feeding was seen after injection of NMU into any of the other hypothalamic areas (Fig. 2B).
Cumulative food intake after intra-PVN injection of NMU remained suppressed at 2, 4, and 24 h (Fig. 3A); however, this was accounted for by the marked suppression of food intake in the first hour post injection. After intraarcuate NMU administration, cumulative food intake after 1 h was not significantly different from that in saline-treated controls (Fig. 3B). A delayed suppression of cumulative food intake was noted after the administration of NMU into the MPO (Fig. 3C). This was accounted for by reduced food consumption between 4 and 8 h post injection (4.3 ± 0.7 g; saline, 6.8 ± 0.6; P < 0.05) and during the dark phase between 8 and 24 h post injection (12.5 ± 1.5 g; saline, 17.9 ± 1.1; P < 0.05).
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A similar pattern of marked behavioral change was noted in the hour after intra-PVN injection of NMU (Fig. 4). A prominent increase in grooming was observed [NMU, 52.8% (22.7–72.2%); saline, 5.6% (0–8.3%); P = 0.004]. NMU-treated animals also exhibited increased locomotor behavior [NMU, 20.8% (11.1–27.8%); saline, 0% (0–2.8%); P = 0.011]. Conversely, the quiescent behaviors of head down while still (H) and sleep (S) were reduced in NMU-treated animals (H: NMU, 4.2% (2.8–25%); saline, 40.3% (36.1–41.7%); P = 0.03; S: NMU, 0% (0–8.3%); saline, 51.4% (16.7–58.3%); P = 0.03]. Despite the reduction in quantity of food eaten, there was no significant reduction in the observed number of feeding episodes in NMU-treated rats compared with saline-treated rats (Fig. 4). All behaviors observed were readily assigned to the predefined treatment categories, and no adverse behaviors were observed in either treatment group.
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). NMU (0.3 nmol) significantly stimulated plasma ACTH (Fig. 5A; NMU, 39.2 ± 5.9 pg/ml; saline, 12.2 ± 2.6; P < 0.001) and corticosterone (Fig. 5B; NMU, 303.6 ± 21.6 ng/ml; saline 171.0 ± 20.9; P < 0.01) at 20 min post injection. No significant stimulation of ACTH or corticosterone was seen at 5 and 10 min post injection of 0.3 nmol NMU (data not shown).
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; 141.9 ± 20.4 fmol/explant; basal release, 92.9 ± 9.4; n = 36; P < 0.01).
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; 100 nM NMU, 5.9 ± 0.92 pmol/explant; basal release, 3.8 ± 0.39; n = 29; P < 0.01). Similarly, 10 and 100 nM NMU stimulated AVP release (Fig. 6C; 100 nM NMU, 124.5 ± 21.8 fmol/explant; basal release, 74.5 ± 7.6; n = 30; P < 0.01). |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the current study, we administered NMU into discrete hypothalamic areas to investigate whether the feeding inhibition can be localized to specific hypothalamic nuclei. An immediate inhibition of feeding was seen in the first hour after PVN and Arc administration of NMU. No early inhibition of food intake was seen after injection of NMU into any of the other hypothalamic nuclei. After PVN injection of NMU, there was inhibition of feeding to 59% of control food intake compared with 76% after Arc injection. Inhibition of food intake in the PVN was dose dependent, with the lowest effective dose being 0.1 nmol NMU. The inhibition of feeding in the PVN may be mediated by NMU2R. Within the hypothalamus, in situ hybridization studies demonstrated that NMU2R is expressed only in the PVN and in ependymal cells lining the third ventricle (15), whereas there is no hypothalamic expression of NMU1R (15). No NMU receptor expression has been demonstrated in the Arc. It is possible that the NMU2R is expressed in the Arc at low levels not detectable by in situ hybridization. Alternatively, the inhibition of feeding in this nucleus may be mediated by another, as yet unidentified, NMU receptor. It is unlikely that the inhibition of feeding seen after arcuate injection of NMU is due to diffusion of peptide to the PVN. No effect on food intake was seen after injection of NMU into the AHA, LHA, DMN, and VMN, all of which are closer to the PVN.
A surprising finding was the delayed inhibition of feeding seen at 4–8 h and 8–24 h after NMU injection into the MPO. The MPO is mainly involved in the control of reproductive function, but c-Fos-like immunoreactivity and neuropeptide Y content increase in the MPO after the ingestion of a palatable meal (40, 41). The anorectic hypothalamic peptide 
MSH also inhibits feeding when administered into the MPO (24). It is unlikely that the effect on food intake in the MPO is due to diffusion of peptide to the PVN, as no effect was seen until 4 h. Also, no similar effect was seen after injection of nuclei much closer to the PVN, such as the AHA. It is possible that this delayed effect is indirect, involving the activation or inhibition of other neuronal regulatory systems.
As NMU is a putative anorectic neurotransmitter, we investigated the effect of leptin on NMU release from hypothalamic explants. Leptin stimulated NMU release in this system. Others have shown that in the presence of low or absent circulating leptin (in fasting rats and in leptin-deficient ob/ob mice), hypothalamic NMU expression is reduced (15). These data taken together suggest that NMU release may be stimulated by leptin, and NMU synthesis may be inhibited in its absence.
The behavioral changes observed after administration of NMU, either icv or into the PVN, were more striking than the inhibition of food intake. Others have reported similar behavioral changes in response to icv NMU (42). It has been postulated that NMU caused locomotor and grooming behaviors via CRH neurons in the PVN, as the behavior pattern was similar to the stress response induced by icv CRH (43, 44, 45). Furthermore, the locomotor and grooming responses to NMU were attenuated by the CRH antagonist -helical CRH-(9–41) or by anti-CRH IgG (42). The locomotor response to NMU was also absent in CRH knockout mice (42). However, CRH neurons involved in the stress response are also located in the central nucleus of the amygdala as well as the hypothalamic PVN (46). It is possible that these neurons may have mediated the effect of icv NMU. We have now demonstrated that administration of NMU directly into the PVN causes a marked increase in grooming and locomotor behaviors. Furthermore, NMU stimulates the release of CRH as well as AVP from hypothalamic explants in vitro. CRH has also been demonstrated to inhibit feeding after icv administration (45). Therefore, hypothalamic NMU has similar effects on feeding and stress-related behaviors as CRH and appears to mediate these actions via the PVN at least in part through CRH release. We hypothesized that in addition to stimulating CRH neurons involved in arousal and stress-related behaviors, NMU may stimulate the hypophysiotrophic CRH/AVP neurons responsible for activation of the HPA axis. NMU administration into the PVN resulted in increased plasma ACTH and corticosterone at 20 min post injection. In combination with the finding that NMU increased the release of CRH and AVP from hypothalamic explants in vitro, this suggests that CRH/AVP neurons projecting to the median eminence are NMU responsive. This is the first report that NMU stimulates the HPA axis at the hypothalamic level.
The lowest effective doses of NMU in the in vivo and in vitro experiments were greater than the amount of NMU released from medial basal hypothalamic explants in vitro. However, due to peptide degradation and the requirement for tissue penetration, the actual concentration of NMU reaching the NMUR on NMU-responsive neurons, both after icv and intranuclear administration in vivo and after application to hypothalamic explants in vitro, will be less than the initial concentration administered. Within the hypothalamus NMU appears to be restricted to a small subgroup of neurons with cell bodies in the Arc and median eminence (13, 15 13, 15) and with projections to several nuclei, particularly the PVN, VMN, DMN, and Arc (13). Although the total amount of NMU released from a hypothalamic explant in vitro may be relatively small, the concentration of NMU achieved in the synaptic cleft between NMU neurons and NMU target neurons is probably much higher. It is possible that the concentration of NMU occurring physiologically at the NMUR of NMU-responsive neurons is comparable to that achieved after the administration of effective doses of NMU in vivo and in vitro. At present this remains speculative, and the physiological significance of the actions of NMU described above remains to be established.
In summary, we present data to suggest that NMU inhibits food intake via an action on the hypothalamic PVN and Arc. Hypothalamic NMU release is stimulated by leptin, as would be expected for a putative satiety signal. NMU inhibits feeding and stimulates stress-related behaviors and the HPA axis via an action on the PVN that appears to involve CRH release.
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Acknowledgments |
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Footnotes |
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Abbreviations: aCSF, Artificial cerebrospinal fluid; AHA, anterior hypothalamic area; Arc, arcuate nucleus; AVP, arginine vasopressin; CNS, central nervous system; CRH-LI, CRH-like immunoreactivity; DMN, dorsomedial nucleus; HPA, hypothalamo-pituitary-adrenal; icv, intracerebroventricular; LHA, lateral hypothalamic area; MPO, medial preoptic area; NMU, neuromedin U; NMU-LI, neuromedin U-like immunoreactivity; PVN, paraventricular nucleus; SON, supraoptic nucleus; VMN, ventromedial nucleus.
Received March 18, 2002.
Accepted for publication July 18, 2002.
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