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Department of Psychology (D.L.W., J.M.K., H.J.G.), University of Pennsylvania, Philadelphia, Pennsylvania 19104; Molecular and Cellular Biology (R.R.B.), Medical University of South Carolina, Charleston, South Carolina 29425; and Department of Biology (T.J.B.), Georgia State University, Atlanta, Georgia 30303
Address all correspondence and requests for reprints to: D. L. Williams, VA Puget Sound Health Care System, 1660 South Columbian Way, S-111-Endo, Seattle, Washington 98108. E-mail: dianalw{at}u.washington.edu.
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Abstract |
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Introduction |
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Current models of melanocortinergic control of energy balance focus on hypothalamic nuclei. The arcuate nucleus (ARC) contains sets of neurons that express agouti-related protein, and those that express proopiomelanocortin (POMC, the precursor of the endogenous MC3/4-R ligand 
-MSH). These neurons project to other hypothalamic structures such as the paraventricular nucleus (PVN) and dorsomedial nucleus, sites where microinjection of a MC3/4-R agonist inhibits food intake (12, 13). Some of the same hypothalamic nuclei also are considered critical for the energy expenditure responses to MC3/4-R stimulation. For example, neuroendocrine responses to hypothalamic MC3/4-R stimulation, such as increased thyroid-releasing hormone release by the PVN, may contribute to the increase in energy expenditure (14, 15, 16). In addition, sympathetic nerve activity, acknowledged as a major stimulus for BAT thermogenic activity, is thought to be influenced by neurons that express MC3/4-R in the PVN and by POMC neurons in the ARC via their direct projections to sympathetic preganglionic neurons in the intermediolateral cell column (IML) of the spinal cord (17, 18).
The case for a hypothalamic melanocortin contribution to the control of energy balance is strong, but there also is evidence that focuses attention on other MC3/4-R populations in the central nervous system. Of particular interest are caudal brainstem regions of clear relevance to ingestive behavior control (19), within which MC4-R are expressed at high density, including the dorsal vagal complex (DVC), parabrachial nucleus (PBN), and nucleus raphe pallidus (RPa) (18, 20). It is already clear that hindbrain MC-R populations are relevant for the control of ingestive behavior. For example, the food intake responses to fourth icv delivery of MTII and SHU9119 (a MC3/4-R antagonist) are as strong as those obtained upon lateral icv delivery (1). Moreover, injections of MTII or SHU9119 into the DVC or PBN induce marked feeding responses with doses below threshold for fourth icv effects (21, 22). The energy expenditure effects of caudal brainstem MC3/4-R treatments have not been evaluated but are plausible in light of the direct and indirect projections from MC-R-rich hindbrain structures to IML neurons, and the correlation between neural activity in areas such as the RPa with BAT thermogenesis (23, 24, 25, 26). Thus, there is an anatomical basis for the suggestion that like hypothalamic MC-R populations, receptors in the hindbrain influence both food intake and sympathetic activation of BAT.
In the present study, we address two hypotheses concerning caudal brainstem MC-R involvement in energy balance: 1) that hindbrain MC3/4-R agonist treatment stimulates uncoupling protein 1 (UCP-1) gene expression in BAT; and 2) that this effect is mediated by a mechanism(s) intrinsic to the caudal brainstem (i.e. independent of hypothalamic involvement). We examined the effect of central MTII treatment on UCP-1 mRNA expression in BAT because UCP-1 is the primary effector of thermogenesis in BAT and is stimulated by sympathetic nerve activation (reviewed in Refs. 27 and 28). Up-regulation of UCP-1 in response to activation of MC3/4-R has not been directly examined, although such an effect would be expected, at least for hypothalamic treatment, based on the previous demonstration of MTII-induced elevation in the activity of sympathetic nerves innervating interscapular BAT (IBAT;10). We affirm this expectation in rats receiving third icv injections of MTII, and further show a comparable increase in UCP-1 expression after fourth icv treatment. That this caudal brainstem-elicited response is indeed mediated by sympathetic efferents is demonstrated by our finding that denervation of IBAT completely blocks the UCP-1 mRNA response to fourth icv MTII treatment. The question of whether there is a hypothalamic contribution to the hindbrain-triggered response is addressed by an experiment in which MTII is delivered to the fourth ventricle of chronic decerebrate rats. An increase in UCP-1 mRNA expression in response to MTII administration in decerebrate rats would add weight to the hypothesis that elevations in energy expenditure can be triggered by caudal brainstem MC3/4-R and would further demonstrate that the production of this response can be mediated entirely by neural circuits within the hindbrain and spinal cord.
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Materials and Methods |
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Intracerebroventricular cannulation
Each rat received a guide cannula (Plastics One, Roanoke, VA; 26-gauge), implanted 2.0 mm above either the third or fourth ventricle, under ketamine (90 mg/kg), xylazine (2.7 mg/kg) and acepromazine (0.64 mg/kg) anesthesia administered by im injection. Third-ventricle cannula placement was 2.0 mm posterior to bregma, -7.0 mm ventral to dura, and on the midline. Fourth-ventricle cannula placement was 2.5 mm anterior to occipital suture, -4.5 mm ventral to dura, and on the midline. The cannula was cemented to four jeweler’s screws attached to the skull, and closed with an obturator. Rats recovered for at least 5 d, during which daily food intake and body weight were recorded. Intracerebroventricular cannula placement was evaluated after recovery from surgery through the measurement of a sympathetically mediated increase in plasma glucose 60 min after icv injection of 210 µg of 5-thio-D-glucose in 2 µl of artificial cerebrospinal fluid (aCSF; Harvard Apparatus, Holliston, MA) (29). Only rats that showed at least a doubling of plasma glucose level in response to this treatment were used in experiments.
Ribonuclease protection assay
To generate a riboprobe for use in ribonuclease protection assays (RPAs), a full-length rat cDNA encoding UCP (GenBank accession no. NM_012682) (30) was digested with HindIII (cuts at nucleotide 683) and BamHI (cuts at nuceotide 1014) to yield a 331-bp gene fragment that was subcloned into the Topo pCRII cloning vector (Invitrogen, Carlsbad, CA). Thereafter, the SP6 and T7 RNAP promoters flanking the multiple cloning site of Topo pCRII were used in in vitro transcription reactions to prepare run-off cRNA transcripts. The cRNA transcribed by one RNAP (RNA polymerase) is the sense strand, whereas the cRNA produced by the other RNAP was radiolabeled with [32P]CTP and used as a riboprobe in RPAs, essentially as described previously (31). Briefly, 2 x 104 cpm of 32P-labeled riboprobe was coprecipitated with 0.5 µg of adipose tissue RNA. An 18S rRNA riboprobe was included as an internal control to ensure that equal amounts of RNA from each sample were used. After ethanol precipitation and suspension in hybridization buffer, RNA was denatured at 80 C and hybridized at 55 C overnight. Unhybridized RNA was digested by adding 300 U of T1 ribonuclease to each sample and incubating at 37 C for 1 h, and the reaction was stopped with 5 mM EDTA. After precipitation, protected double-stranded RNA was resuspended in dye and electrophoretically resolved on 6% denaturing polyacrylamide gels containing 8 M urea. The gels were exposed to film, and the autoradiographs were scanned with a densitometer. Known amounts of sense strand standards were included in each assay to allow quantification of protected mRNA. Because the densitometric area of the autoradiographic bands is a linear function of the amount of sense strand added, we were able to generate a standard curve to quantify the message protected in each lane.
Experiment 1
Design and procedures.
Twenty-five rats were implanted with third or fourth icv cannulae as described above. Our injection schedule was modeled after that used by Kotz and colleagues (32). All rats received three injections over the course of 24 h, separated by 12-h intervals. Injections took place in the middle of the light or dark phase. Each subject was assigned to one of three groups, as follows: 1) aCSF, ad libitum access to food (fourth icv, n = 4; third icv, n = 4); 2) MTII, ad libitum access to food (fourth icv, n = 5; third icv, n = 5); and 3) aCSF, pair-fed to MTII-treated rats’ intake (fourth icv, n = 4; third icv, n = 3). For weight-related dependent measures, the pair-fed group was included to distinguish between the effect of drug and the effect of reduced intake. MTII was prepared by dissolving the peptide in aCSF. Injections were administered through 28-G stainless steel tubing that extended 2 mm below the guide cannula. A 2-µl volume of drug or aCSF was injected over 2 min using a Hamilton microsyringe. The injector was left in place for another minute before removal. The dose of 0.33 nmol MTII/injection was chosen because of its efficacy at decreasing food intake (1, 33). Immediately before the third injection, food was removed from all subjects. Two hours after the third injection, rats were euthanized with CO2 gas. Retroperitoneal and epididymal white adipose tissue (RWAT, EWAT) and IBAT was dissected and weighed. IBAT was preserved in RNAlater (Ambion, Austin, TX) for UCP-1 mRNA analysis (as described above).
Statistical analysis.
Two-way ANOVA [site of injection (third vs. fourth icv) X treatment group (aCSF, MTII)] was used to evaluate effects on UCP-1 mRNA level. For RWAT weight, EWAT weight, food intake, and body weight change during the 24 h of the experiment, three treatment groups were compared in the ANOVA: aCSF, MTII, and aCSF pair fed. Tukey’s honestly significant difference method was used for post hoc comparisons where appropriate.
Experiment 2
BAT denervation.
Unliateral denervation of IBAT was performed as previously described (34) in anesthetized animals. Briefly, an incision was made anterior to the IBAT and the tissue was separated from the underlying muscle by blunt dissection. The intercostal nerve bundles entering each side of the pad were visualized, and a section of each nerve bundle was removed on one side of the pad. Half of the subjects were denervated on the left, and the other half were denervated on the right side. During the same surgery, rats were implanted with fourth icv cannulas as described above.
Surgical denervation of BAT was verified by measuring norepinephrine (NE) content in BAT using reverse-phase HPLC with electrochemical detection essentially after our modification (35) of the method of Mefford (36). Briefly, half of each hemisphere of BAT was thawed and homogenized in a solution containing 20 ng of dihydroxybenzylamine (internal standard) in 0.2 M perchloric acid and 1 mg /ml ascorbic acid. After centrifugation, catecholamines were extracted from the homogenate with alumina and eluted into 0.2 M perchloric acid and 1 mg /ml ascorbic acid. Catecholamines were assayed using an ESA (Bedford, MA) HPLC system with electrochemical detection (Cuolochem II). The mobile phase was Cat-A-Phase II and the column was a C-18 reverse phase column. Results were analyzed offline and expressed as ng of NE/g of BAT.
Design and procedures.
Rats were given three injections of aCSF (2 µl) or MTII (0.33 nmol in 2 µl aCSF) into the fourth ventricle, on the same schedule as that described above for experiment 1. All rats were given ad libitum access to food in this experiment. Two hours after the third injection, the animals were euthanized with CO2 gas, and IBAT was dissected and weighed. Half of each hemisphere of IBAT was preserved in RNAlater (Ambion, Austin, TX) for UCP-1 mRNA analysis (as described above), and the other half was rapidly frozen with methylbutane and dry ice for HPLC.
Statistical analysis.
The effects of surgical denervation and MTII treatment on UCP-1 mRNA level in IBAT were assessed via two-way ANOVA [denervation (intact vs. denervated BAT hemisphere) X treatment group (vehicle vs. drug)]. Post hoc comparisons were made using Bonferroni-adjusted t tests where appropriate.
Experiment 3
Decerebration surgery.
Supracollicular decerebration was performed in two stages separated by at least 1 wk, as previously described (37). Neurologically intact control rats were implanted with fourth icv cannulae, and decerebrate rats received fourth icv cannulae during the second hemisection surgery. Animals recovered for at least 1 wk before the experiment. The completeness of the intended transection was verified histologically after the experiment.
Subject maintenance.
All nutrition was supplied via four daily gastric intubations of 9 ml of liquid diet (1:1 Borden’s sweetened condensed milk/water, with 1 ml Polyvisol with iron added per 600 ml of diet). This maintenance diet provides 76 kcal/d. Feedings were separated by intervals of at least 2 h. All subjects gained weight on this diet during the period of recovery from surgery, but there were no group differences (chronic decerebrate mean, 346.4 g; control mean, 357.1 g).
Design and procedures.
Half of the chronic decerebrate (n = 12) and neurologically intact control (n = 12) groups were given three fourth icv injections of aCSF (2 µl), and the other half were given MTII (0.33 nmol in 2 µl aCSF). As for experiments 1 and 2, there were three injections over a 24-h period, separated by 12-h intervals. Rats were tube-fed as usual during the first 12 h between injections, but were not fed thereafter. Two hours after the final injection, rats were euthanized with CO2 gas. RWAT, EWAT, and IBAT was dissected and weighed. IBAT was preserved in RNAlater (Ambion) for UCP-1 mRNA analysis (as described above).
Statistical analysis.
Two-way ANOVA (decerebration X drug treatment) was used to evaluate effects on UCP-1 mRNA level, RWAT weight, and EWAT weight. Tukey’s honestly significant difference method was used for post hoc comparisons where appropriate.
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Results |
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, central MTII treatment significantly elevated IBAT UCP-1 mRNA (see Fig. 2 for a representative autoradiograph). Statistical support for these conclusions is derived from the significant main effect of drug treatment [F(1, 14) = 14.34, P < 0.01] and the post hoc comparisons revealing that MTII-treated rats had significantly higher UCP-1 mRNA levels than aCSF-treated ad libitum-fed rats (P < 0.01). The observed effect of MTII on UCP-1 expression did not depend on site of administration, as demonstrated by the lack of a main effect [F (1, 14) = 1.20, not significant (NS)] or interaction [F (1, 14) = 0.72, NS]).
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). There were significant main effects of treatment group on WAT weight [RWAT F (2, 18) = 5.81, P < 0.05; EWAT F (2, 19) = 7.5, P < 0.01], but in each case, the weights of the MTII-treated and vehicle-treated pair-fed groups were not distinguishable. Both MTII-treatment and pair-feeding significantly reduced WAT weight compared with vehicle treatment in ad libitum-fed rats (all P < 0.05). This finding should not be taken to indicate that central MTII treatment does not stimulate WAT lipolysis; more direct investigation of lipolysis in WAT would be required to make such a conclusion (see38). The effects on WAT size did not depend on the ventricle injected [main effect of injection site: RWAT, F (1, 18) = 0.39, NS; EWAT, F (1, 19) = 0.63, NS].
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; F(1, 14) = 62.83, P < 0.001], with no effect of injection site [F(1, 14) = 1.22, NS]. Rats with reduced intake due to MTII treatment or pair feeding lost a significant amount of body weight relative to aCSF-treated rats allowed to ingest ad libitum [F(2, 19) = 19.91, P < 0.001, post hoc P < 0.001]. MTII injection did not reduce body weight to a greater degree than did pair feeding. Site of injection also had no influence on body weight.
Experiment 2
IBAT denervations were confirmed with HPLC as described above. Denervation of BAT reduced NE content by 83.4%, on average. Subjects were removed from the analysis if the NE content difference between intact and denervated BAT was less than 60% (only one such case was observed).
As shown in Fig. 3, MTII treatment increased UCP-1 mRNA expression only in the intact IBAT hemisphere [interaction between drug and denervation F (1, 7) = 8.60, P < 0.02; post hoc comparisons: 1) intact IBAT, vehicle vs. MTII P < 0.05; 2) denervated IBAT, vehicle vs. MTII NS; 3) MTII-treated group, intact vs. denervated IBAT P < 0.05]. The results clearly indicate that the MTII-induced rise in UCP-1 mRNA expression is mediated by sympathetic nerve activity.
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shows that UCP-1 mRNA was up-regulated by MTII treatment in both neurologically intact and decerebrate rats [F (1, 20) = 8.41, P < 0.01]. Baseline UCP-1 mRNA expression was not altered by decerebration [F (1, 20) = 2.51, NS]. Despite the apparent difference in the magnitude of the response between intact and decerebrate rats, there was no significant interaction between decerebration and drug treatment [F (1, 20) = 2.14, NS]. Not surprisingly, in light of the continued gavage-feeding of all rats throughout the experiment, MTII treatment did not affect body weight or the size of either WAT depot examined (see Table 2).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The substantive contribution of the experiments reported here lies in expanding the range of MC-R that are potentially important for the control of energy expenditure beyond the hypothalamus. The results are consistent with both stated hypotheses: that there is an independent trigger for the increase in UCP-1 mRNA after MC3/4-R stimulation within the caudal brainstem, and that this response can be mediated by circuitry contained entirely within the caudal brainstem and spinal cord.
The response to fourth icv administration of MTII seen in neurologically intact rats (experiments 1 and 2) supports the suggestion that MC-R in the hindbrain can activate sympathetic outflow to BAT. The fourth icv results in intact rats alone, however, do not address the extent of the central network involved in the mediation of the UCP-1 response. Indeed, one could hypothesize a hypothalamic contribution as part of a mechanism involving an ascending pathway driven by caudal brainstem MC3/4-R stimulation, hypothalamic integration, and a descending command to the sympathetic effectors. Such a long-loop arrangement is discounted in decerebrate rats with transections that eliminate all ascending projections to the hypothalamus, as well as any means for hypothalamic structures to directly engage sympathetic premotor neurons. MTII treatment did significantly elevate UCP-1 gene expression in decerebrate rats, and this effect was of appreciable magnitude (
50% increase) relative to those generally reported (e.g. Refs. 32 and 39). The UCP-1 response in decerebrates was not statistically distinguishable from that seen in intact controls (i.e. no group X treatment interaction), although the average effect size was smaller in decerebrates than in the controls. In any event, the demonstrable UCP-1 response in decerebrate rats, which was at least qualitatively similar to that observed in controls, affirms a caudal brainstem MC-R trigger for the response and, moreover, supports the hypothesis that there is mediating circuitry intrinsic to the brainstem and spinal cord through which changes in energy expenditure can be elicited.
The positive indications of a role for caudal brainstem MC-R in the control of energy expenditure do not discount potentially important hypothalamic contributions. Dual (or multiple) MC3/4-R triggers already have been demonstrated for feeding responses to MC3/4-R stimulation and antagonism, with ventricle-subthreshold doses of receptor ligands delivered to the hypothalamic (12) and caudal brainstem (21, 22) parenchyma, respectively, yielding significant and robust ingestive effects. We maintain a working hypothesis that energy expenditure responses are also subject to both hypothalamic and hindbrain melanocortinergic control. A multilevel control principle raises a number of issues for further investigation, including interactions between the relevant hypothalamic and brainstem structures, and sites of convergence for pathways linking the anatomically disparate MC-R triggers with the sympathetic effectors.
A better understanding of the brainstem contribution to melanocortinergic control of energy expenditure requires the localization of the MC-R that mediate the effects of fourth icv MTII administration. Although we think it unlikely, the possibility that the observed effects reflect diffusion of the agonist to receptors in the spinal cord has not been formally ruled out. The RPa is one candidate brainstem site of MTII action, given that pharmacological disinhibition of RPa neurons elicits increased firing of sympathetic nerves innervating BAT (20, 40, 41). MC4-R-bearing neurons in the nucleus of the solitary tract (NTS) may also give rise to thermogenic responses, either through direct projections to IML or indirectly, through projections to other nuclei within the hindbrain, such as the ventrolateral medulla (42). As is the case for the feeding response to MTII (21, 22), there may be more than one MC-R population in the caudal brainstem from which thermogenic responses can be initiated.
Although the present results reveal an effect of brainstem MC-R activation, they do not speak to the source of the endogenous ligand for the receptors stimulated by fourth icv infusion of MTII. There are only two known possibilities: POMC neurons in the ARC and those in the NTS (43, 44, 45). The ARC POMC neurons project to other areas of the hypothalamus and elsewhere in the forebrain, but they also project to the hindbrain and spinal cord (44). The POMC neurons of the NTS project primarily within the dorsal vagal complex and to other brainstem structures (46, 47). It is possible, then, that the MC-R stimulated by fourth icv treatments are normally supplied by POMC fibers originating from ARC, from NTS, or from both sites. A contribution of the NTS is an intriguing possibility, given that this region receives signals correlated with metabolic status that are known to influence energy expenditure (e.g. leptin) (48, 49). Very little, however, can be said about the POMC neurons in the NTS. Almost no information is available about colocalization of receptors and other neurotransmitters, or about the physiology of these neurons; and at this point, no functional role has been assigned to this potentially interesting POMC cell population. Considerably more information is available about the POMC neurons in ARC, which figure prominently in the contemporary model of central nervous system control of energy balance (e.g. Ref.50). If ARC POMC cells can be implicated here, then there would be multiple pathways through which the ARC may regulate sympathetic outflow: a direct projection to IML; an indirect projection to IML via the PVN; and an indirect projection to IML via a caudal brainstem relay. The issue of ARC and NTS contributions to melanocortinergic control of energy expenditure, as well as multilevel interactions between receptor-containing structures, are important topics for future research.
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Footnotes |
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Abbreviations: aCSF, Artificial cerebrospinal fluid; ARC, arcuate nucleus; BAT, brown adipose tissue; DVC, dorsal vagal complex; EWAT, epididymal white adipose tissue; IBAT, interscapular BAT; icv, intracerebroventricular; IML, intermediolateral cell column; MC3/4-R, melanocortin 3 and 4 receptor; MTII, melanotan II; NE, norepinephrine; NS, not significant; NTS, nucleus of the solitary tract; PBN, parabrachial nucleus; POMC, proopiomelanocortin; PVN, paraventricular nucleus; RNAP, RNA polymerase; RPaicv, nucleus raphe pallidus; RWAT, retroperitoneal white adipose tissue; UCP-1, uncoupling protein 1.
Received April 9, 2003.
Accepted for publication July 23, 2003.
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References |
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-melanocyte-stimulating hormone. Diabetes 49:177–182[Abstract]
-Melanocyte-stimulating hormone is contained in nerve terminals innervating thyrotropin-releasing hormone-synthesizing neurons in the hypothalamic paraventricular nucleus and prevents fasting-induced suppression of prothyrotropin-releasing hormone gene expression. J Neurosci 20:1550–1558-MSH) in brainstem baroreceptor areas of the rat. Brain Res 436:323–338[CrossRef][Medline]
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 B. CANNON and J. NEDERGAARD Brown Adipose Tissue: Function and Physiological Significance Physiol Rev, January 1, 2004; 84(1): 277 - 359. [Abstract] [Full Text] [PDF]
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K. Takahashi The Brainstem Is a Key Target for Neuroendocrine Research on Obesity Endocrinology, November 1, 2003; 144(11): 4690 - 4691. [Full Text] [PDF]
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