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NEUROENDOCRINOLOGY |
Department of Medicine, Division of Endocrinology and Diabetology, University of Geneva, Faculty of Medicine, 1211 Geneva 14, Switzerland
Address all correspondence and requests for reprints to: Dr. F. Rohner-Jeanrenaud, Hôpitaux Universitaires de Genève, Division of Endocrinology and Diabetology, 24, rue Micheli-du-Crest, 1211 Geneva 14, Switzerland. E-mail: . f.rohner-jeanrenaud{at}hcuge.ch
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Abstract |
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-MSH agonist, MTII, on body weight and the expression of uncoupling proteins (UCPs) and carnitine palmitoyltransferase-1 were determined in lean and genetically obese fa/fa rats by comparing MTII-treated animals with two different control groups, one being ad libitum fed, the other pair-fed to the amount of food consumed by MTII-treated rats. MTII treatment of lean and obese rats lowered food intake and body weight, the effects being more marked in obese than in lean rats. In both groups, MTII administration suppressed the increased plasma FFA levels brought about by food restriction. In lean rats, MTII prevented the decrease in brown adipose tissue UCP1, UCP2, and UCP3 expression and muscle UCP3 occurring during food restriction. In obese animals, MTII markedly increased brown adipose tissue (7-fold) and muscle (2.5-fold) UCP3 expression. The decrease in liver carnitine palmitoyltransferase-1 elicited by food restriction in lean and obese rats was prevented by MTII administration. In summary, the effects of MTII resemble those of leptin and are more marked in obese than in lean animals, in keeping with their reported reduced endogenous melanocortin tone. Melanocortin agonists may be useful in the treatment of obesity associated with impaired leptin signaling. |
Introduction |
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-MSH, posttranslationally cleaved from POMC, is recognized as being of importance in the regulation of body weight homeostasis. This was based on the finding that two of the five cloned melanocortin receptors (1), the MC3 and MC4 receptors, were found to be primarily expressed in the brain (2). The importance of the melanocortin system was further supported by the following observations: The intracerebroventricular (icv) injection of ACTH (1–24) was reported to acutely inhibit feeding in rodents (3, 4). The icv administration of the synthetic cyclic lactam melanocortin agonist, melanotan-II (MTII), dose dependently inhibited food intake in normal mice (5), and it decreased the hyperphagia of genetically obese mice (ob/ob and agouti yellow) as well as that induced by icv NPY injection (5). When given peripherally, MTII produced a similar reduction in food intake, provided that the doses were 30–40 times higher than those used centrally, suggesting that melanocortins were acting within the brain (5). The icv administration of synthetic melanocortin receptor antagonists had stimulatory effects on food intake and body weight (5, 6, 7, 8). The knockout of the POMC gene produced severe obesity, and the excessive fat deposition was brought toward normal by the chronic injection of a stable - MSH agonist (9). The targeted disruption of the MC3 and/or MC4 receptor gene in mice resulted in obesity (10, 11, 12). In humans, the existence of MC4 receptor gene mutations was described in a relatively large percentage of obese patients (13, 14, 15, 16, 17). The melanocortin system was also shown to be an important catabolic effector of leptin. Thus, central leptin infusion was shown to stimulate the expression of POMC in the arcuate nucleus after binding to and activation of its long receptor isoform located on POMC neurons (18, 19, 20, 21, 22). Leptin-deficient mice were reported to have reduced POMC mRNA in the arcuate nucleus, a defect that could be normalized on leptin treatment (19, 23, 24). The central effects of leptin on food intake and body weight were shown to be blocked by a melanocortin receptor antagonist (7).
In addition to its role in inhibiting food intake and body weight gain, leptin has been reported to favor lipid utilization in adipose and nonadipose tissues, as assessed by the measurement of a leptin-induced increase in the expression of carnitine palmitoyltransferase-1 expression (CPT-1) in particular (25, 26, 27). Leptin has also been shown to stimulate the expression of uncoupling protein (UCP)-1, -2, and -3 at the level of various tissues, compared with the effects of imposed decreased food intake (mimicking the action of leptin on this parameter) that reduced such gene expression (28, 29). Together these data are consistent with the reported stimulatory effect of leptin on the energy expenditure process and the activity of the sympathetic nervous system (30, 31, 32, 33). Of interest are the observations that the stimulatory effects of leptin on the expression of UCPs and on the sympathetic nervous system activity have been shown to be mediated by the melanocortin system (34, 35, 36).
Because the melanocortin system appears to be located downstream of the hypothalamic leptin signaling pathway (37), it was hypothesized, in the present study, that melanocortin agonists would affect some of the parameters that are regulated by leptin, i.e. not only food intake and body weight but also the expression of UCPs and CPT-1 in normal rats and would be efficient on these parameters in obesity syndromes brought about by deficiencies in leptin signaling or to the presence of leptin resistance, as was recently reported (38, 39).
Based on these considerations, the present experiments aimed at assessing, in lean and genetically obese fa/fa rats, the effects of a 3-d peripheral administration of MTII on the plasma levels of hormones and metabolites involved in lipid metabolism and the mRNA expression of UCPs at the level of different tissues and CPT-1.
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Materials and Methods |
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The cyclic lactam MTII ([Ac-Nle4, Asp5, D-Phe7, Lys10]-cyclo--MSH (4, 5, 6, 7, 8, 9, 10) (amide, Juro, Luzern, Switzerland) was administered daily by the ip route at a dose of 2 mg/kg for 3 d (d 0-d 3). This dosage was chosen on the basis of preliminary experiments that showed that lower amounts of MTII were completely inefficient in decreasing food intake and body weight in lean rats (data not shown). Saline was used as solvent and was injected to controls. In lean and obese rats, three groups of rats were investigated: 1) rats injected with saline and allowed to eat ad libitum (referred to as controls); 2) rats injected with MTII and having free access to food (MTII); and 3) rats injected with saline but pair-fed to the amount of food consumed by MTII-treated animals (pair-fed). The pair-feeding regimen was performed as follows: The average daily food intake of the MTII-treated group was calculated. One-third of this amount of food was given in the morning (0800 h), and the remaining two-thirds were given before the extinction of the lights (1800 h), based on preliminary studies of food consumption during the day and the night. On the morning of each experimental day, a blood sample was collected, in unrestrained animals, for the determination of plasma FFA levels, using a previously described unstressful tail-clip sampling procedure (40). The sample of d 0 was taken just before the ip bolus injection of saline or MTII. At the end of the 3-d experimental period (6 h after the last ip bolus injection of MTII), the animals were killed by decapitation and various tissues were collected.
All procedures used were approved by the Office Vétérinaire Fédéral et Cantonal (Geneva, Switzerland).
Plasma hormones and metabolites measurements
Plasma insulin concentrations were measured by RIA (41). Plasma leptin levels were determined using a commercial kit for rat leptin (Linco Research, Inc., St. Louis, MO). Plasma glucose and FFA concentrations were determined using kits from Boehringer (Mannheim, Germany) and Wako Chemicals GmbH (Neuss, Germany), respectively.
Northern blot analysis
Total RNA was prepared from brown adipose tissue (BAT) and a red fiber-type muscle (red quadriceps) using the Trizol reagent (Life Technologies, Inc., Rockville, MD). Aliquots of 10 µg were size fractionated on 1.5% agarose gels, and blots were hybridized (Quikhyb, Stratagene, La Jolla, CA) to random primed labeled cDNAs for UCP1 (42), UCP2 (43), UCP3 (GenBank accession no. U92069), and glycerol-3-phosphate dehydrogenase (G3PDH) (CLONTECH Laboratories, Inc., Palo Alto, CA). Autoradiographs (X-OMAT-AR film, Kodak, Rochester, NY) were quantified by densitometry using the ImageQuant software (Molecular Dynamics, Sunnyvale, CA). Abundance of UCP1, UCP2, and UCP3 mRNA relative to that of G3PDH in MTII-treated and pair-fed rats was expressed as a percentage of the values obtained in the corresponding ad libitum-fed vehicle-infused control animals (set at 100%). Only signals obtained on the same Northern blot were compared.
Quantitative RT-PCR procedure
Total RNA was extracted from liver and epididymal white adipose tissue (WAT) using the trysol procedure as above. RNA integrity was assessed by performing a 1% agarose-gel electrophoresis in 1x Tris-borate-EDTA buffer, and its concentration was determined by spectrophotometry. Complementary DNA templates for RT-PCR were obtained using 2.5 µg total RNA. Reverse transcription reaction was performed with random hexamers (Microsynth, Geneva, Switzerland); dNTPs; the RNase inhibitor, Rnasin (Catalys, Promega Corp., Madison, WI); and the M-MLV-RT enzyme kit (Life Technologies, Inc.).
The real-time PCR (Lightcycler, Roche Diagnostics, Basel, Switzerland) reaction is an automated quantitative PCR obtained by the continuous monitoring of the fluorescence emitted on binding of the SYBR Green I dye to the double-stranded DNA after each amplification cycle. Amplification of cyclophilin A and CPT-1 was performed with the SYBR Green I DNA master kit (Roche Diagnostics, Mannheim, Germany), according to the light cycler standard protocol, using about 70 ng template cDNA. Primers for cyclophilin and the isoform of CPT-1 (specific liver isoform, also present in WAT [44 ]), used at a final concentration of 0.5 µM were designed on-line with Primer 3 software (http://www-genome.wi.mit.edu/cgi-bin/primer/primer3_www.cgi) and synthesized by Microsynth Gmbh, (Balgach, Switzerland). They were as follows: cyclophilin A (sense primer 5'-AGCACTGGGGAGAAAGGATT-3' starting at 166; antisense primer 5'-CATGCCTTCTTTCACCTTCC-3' starting at 471, product size: 306; and CPT-1 isoform (sense primer 5'-TACTGACACAGGCAGCCAAA starting at 3374; antisense primer 5'-GGATGGCATGTGGGTAAAAG starting at 3576, product size 203 bp).
The annealing temperatures were 60 C for CPT-1 and 57 C for cyclophilin primer sets. After each run, a relative quantification of amplified PCR products in the different samples was performed. For this purpose, standard curves were constructed for the gene of interest as well as for cyclophilin used as the housekeeping gene. The results are expressed as the ratio between the concentration of the target gene and that of cyclophilin.
Statistical significance
The results were analyzed by one-way ANOVA followed by the Tukey procedure for multiple comparisons. The calculations were performed using the Sigma STAT software (SPSS, Inc., Chicago, IL). A P value less than 0.05 was considered statistically significant.
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Results |
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(left panel), food intake of ad libitum-fed lean controls slightly decreased during the experimental period, compared with the initial food intake, before the experiment (d 0). Food intake of lean MTII-treated rats and the pair-fed group was consistently lower than that of ad libitum-fed controls. This decreased food intake failed to reach statistical significance when individual time points were considered. However, when the overall food consumption during the entire experimental period was calculated, a significant 24% decrease in food intake was observed in MTII-treated and pair-fed rats relative to the ad libitum-fed control group (39.8 ± 1.6 g for MTII-treated and pair-fed rats vs. 52.4 ± 2.3 g for ad libitum-fed controls, P < 0.0025). As further shown by Fig. 1 (right panel), the MTII treatment had a pronounced effect in decreasing food intake in obese rats, a decrease that reached statistical significance on each single experimental day. The reduction in food intake observed in MTII-treated obese rats was qualitatively and quantitatively mimicked by pair-feeding. In MTII-treated and pair-fed obese rats, overall food consumption during the entire experimental period was lowered by 37%, compared with ad libitum-fed controls (49.4 ± 2.0 g for MTII-treated and pair-fed rats vs. 78.4 ± 3.4 g for ad libitum-fed controls, P < 0.001).
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(left panel), ad libitum-fed lean controls exhibited a slight body weight gain, but both pair-fed and MTII-treated lean rats lost weight during the experimental period. Cumulative body weight changes (calculated as areas under the curves) were plus 3.2 ± 0.1 g for ad libitum-fed lean animals, minus 16.8 ± 3.8 g for pair-fed rats and minus 19.3 ± 3.7 g for the MTII-treated group (P < 0.01 for pair-fed and MTII-treated rats vs. ad libitum-fed controls). In obese animals, compared with ad libitum-fed controls, which gained weight, the MTII treatment produced a rapid (within 1 d), marked and lasting body weight loss. A similar pattern of body weight loss was observed in the pair-fed group of obese animals (Fig. 2, right panel).
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. In both lean and obese rats, MTII treatment was accompanied by FFA levels that remained at low values, similar to those measured in the ad libitum-fed control groups. In contrast, plasma FFA levels were higher in pair-fed than in ad libitum-fed lean and obese controls. The pair-feeding effect was more marked in the obese than in the lean group, an observation that was strengthened by the following calculations. Because at d 0 plasma FFA levels were the same in all groups of rats, surface areas over baseline for 3 d were determined and compared. As already suggested by Fig. 3, surface areas were found to be close to nil in the ad libitum-fed lean and obese controls as well as in the respective MTII-treated animals. In contrast, surfaces areas were 0.82 ± 0.28 mmol/liter x 3 d in pair-fed lean, and twice as high in pair-fed obese rats (1.71 ± 0.31 mmol/liter x 3 d, P < 0.05).
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). In obese rats, insulinemia and leptinemia were not significantly changed by either pair-feeding or MTII administration (Table 1).
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(left panel), relative to the expression of BAT UCP1, UCP2, and UCP3 measured in ad libitum-fed lean controls, that of lean rats submitted to the pair-feeding regimen was markedly decreased. MTII treatment of lean animals prevented such decreases, actually maintaining the expression of BAT UCPs at the same levels as those of ad libitum-fed controls.
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(right panel). As may be seen, pair-feeding produced a small but significant decrease in the expression of UCP1 only, not in that of UCP2 or UCP3. Furthermore, although MTII treatment of obese rats had no effect on BAT UCP1 and UCP2 expression, it markedly increased (by 7-fold relative to controls) that of UCP3 (Fig. 4, right panel).
As illustrated by Fig. 5, UCP3 expression in red quadriceps muscle was decreased by pair-feeding in both lean and obese animals, relative to the respective ad libitum-fed controls. MTII treatment of lean rats partly maintained this expression at the levels of the ad libitum-fed control group. In obese rats, MTII treatment resulted in a marked stimulation (2.5-fold) in muscle UCP3 expression, relative to that of ad libitum-fed controls.
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. In lean rats, pair-feeding produced a decrease in liver and WAT CPT-1 expression, relative to values of ad libitum-fed controls, decreases that were prevented from occurring by MTII treatment. A similar observation was made for CPT-1 expression in the liver of obese animals. In adipose tissue of obese rats, pair-feeding did not modify CPT-1 expression, but the latter was stimulated 1.6-fold by MTII treatment.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-MSH analog, MTII, in lean and genetically obese Zucker (fa/fa) rats with impaired leptin signaling (mutation of the leptin receptor gene). We observed that the daily ip administration of MTII inhibited food intake over the 3-d experimental period in both lean and obese fa/fa rats, the effect being most marked in the obese group. The effect of MTII in reducing food intake was accompanied by the occurrence of decreased body weight gain, an effect that was also most marked in the obese group.
As already mentioned, among the five melanocortin receptors cloned (1), the MC3 and MC4 receptors are the most important ones in mediating the effects of melanocortins in decreasing food intake and body weight (2, 10, 11, 12, 45). MTII, the melanocortin agonist used in the present study, has been shown to interact with several melanocortin receptor subtypes (45). Previous observations suggest, however, that the inhibitory effects of MTII on food intake and body weight may be mediated by its binding to the MC4 receptor. Thus, central MTII administration is effective in reducing food intake at much lower doses than those needed to elicit similar effects on peripheral injection, in keeping with the observation that the MC4 is the most abundant melanocortin receptor in the brain (46). Also, the icv injection of SHU 9119, an MC3/MC4 receptor antagonist with partial MC1 and MC5 receptor agonist activity (47) has been shown to cancel the dose-dependent inhibitory effect of icv MTII on food intake (48). Finally, the affinity of MTII for the MC4 receptor is five times higher than that for the MC3 receptor (45) and, importantly, MTII fails to induce an anorectic response in MC4 knockout mice (49).
The observation, made in the present study, of a greater food intake and body weight response to the melanocortin receptor agonist in the obese than in the lean group is in agreement with other results also obtained in Zucker (fa/fa) rats (38). The underlying mechanisms responsible for such an increased response to the agonist in the obese group are not elucidated as yet. They could be related to a reduced production of endogenous melanocortins, as partly suggested by the observation of an actual decrease in -MSH-like immunoreactivity in the paraventricular nucleus of another type of obesity in rodents, that brought about by high-fat feeding (39). Thus, a reduced -MSH production in obese fa/fa animals could be responsible via a down-regulation process for the increased density of MC4 receptors reported to occur in several hypothalamic nuclei of other obese rats (50). Such increased MC4 receptor density could, in turn, be the cause of the greater responsiveness to MTII in the obese group, as observed here. The actual understanding of the difference in the response to MTII in lean and obese rats will be complex, when one realizes that the MC4 receptor is present in virtually all brain regions, including the cortex, thalamus, hypothalamus, brain stem, and spinal cord (45) and that final MTII effects may also depend on the production of endogenous melanocortin receptor antagonists, such as the agouti-related peptide. It should be mentioned that, with regard to the sensitivity to melanocortin of obese animals, that of the cardiovascular and sympathetic nervous system of high-fat-fed rats, was reported to be decreased rather than increased (51). This indicates that the responses to MTII depend on the system considered.
In addition to measuring food intake and body weight changes, we investigated the peripheral metabolic consequences of MTII administration. For this purpose and to distinguish between the effects of MTII that are related, or not, to the decreased food intake and body weight gain, the metabolic effects of decreased food intake per se were evaluated by imposing a pair-feeding regimen to groups of lean and obese control animals.
In lean rats, we observed that pair-feeding resulted, relative to values observed in ad libitum-fed controls, in decreases in the expression of BAT UCP-1, -2, and -3, muscle UCP3, and CPT-1 in the liver and WAT. These changes were accompanied, again compared with ad libitum-fed controls, by relative increases in plasma FFA levels.
The effects of MTII administration in lean animals were to maintain to normal or to near-normal values the expression of BAT UCP-1, -2, -3, muscle UCP3, and CPT-1 in the liver and WAT. The effects of MTII on BAT just mentioned are in keeping with the observation of an MTII-induced increased activity of the sympathetic nerves innervating this thermogenic tissue (35). In MTII-treated lean rats, there was no increase in plasma FFA levels, in contrast to what was observed in the pair-fed lean group. This is likely because of the fact that, in the presence of MTII, FFA were oxidized or used as fuels for thermogenesis via, respectively, CPT-1 and UCPs, but such was not the case in pair-feeding.
In obese animals, relative to ad libitum-fed controls, food restriction obtained by pair-feeding resulted in only small decreases in the expression of BAT UCP1 and muscle UCP3 without alteration in that of BAT UCP2 and UCP3. Pair-feeding of obese rats induced a decreased expression of CPT-1 in the liver, not in WAT. These changes were accompanied by definite increases in plasma FFA levels.
MTII administration to obese rats markedly increased the expression of BAT and muscle UCP3 (7- and 2.5-fold, respectively), prevented the occurrence of the pair-feeding-elicited decrease in hepatic CPT-1 expression, and actually stimulated CPT-1 expression in adipose tissue. These effects of MTII were accompanied, relative to pair-fed controls, by increased fatty acid utilization because plasma FFA levels of MTII-treated obese rats failed to rise as they did in pair-fed obese controls. By calculating FFA surface areas over baseline (Fig. 3), fatty acid utilization in the obese group was found to be twice as high as that of lean rats. This is viewed as a likely consequence of the marked increases in mRNA expression of BAT and muscle UCP3 as well as in that of hepatic and adipose tissue CPT-1. Thus, in the obese group, the MTII effects are at the same time more selective and more potent than those observed in lean animals. Such a viewpoint is in keeping with the report showing that central MTII administration in lean and genetically obese fa/fa rats resulted in decreased respiratory quotient values, with an increase in the proportion of energy dissipation derived from fat, the obese animals being more responsive to such MTII effects than their lean littermates (38).
Considering that the melanocortin system is an important catabolic effector of leptin (37), it should be recalled that leptin, in addition to its ability to decrease food intake, body weight (52, 53), and fat mass (54, 55), has been shown by our laboratory to stimulate the expression of BAT UCP1, UCP2, UCP3, and muscle UCP3, relative to pair-fed controls (28, 29). Similar results were also reported by others, although, in some instances, leptin also increased UCP expression relative to those measured in ad libitum-fed controls (56, 57, 58, 59). These observations are consistent with other reports showing that leptin increases thermogenesis and has a stimulatory influence on lipid utilization by several peripheral tissues (27, 60). Additionally, in view of the recent observation that muscle mitochondria of UCP3 knockout mice produce more reactive oxygen species than those of controls (61), it may be thought that leptin could also play a role in the protection against excessive oxidative stress in skeletal muscle.
Because peripheral MTII administration produces the same effects as those elicited by leptin, it may be suggested that MTII acts downstream of leptin signaling. This would be in keeping with the observation that the central effects of leptin on food intake and body weight are blocked by a melanocortin antagonist (7). However, as reported elsewhere (62), melanocortins could have effects that are independent from the action of leptin, despite their resemblance with the effects of this hormone (62). Thus, based on the observations that NPY neurons exert a regulatory influence on POMC neurons (63), it could be envisaged that melanocortins act, either directly by decreasing the activity of the NPY system through the presence of MC3 receptors on NPY neurons (64) or indirectly by modulating the activity of other neuropeptides, such as POMC, involved in the regulation of body weight homeostasis, as recently proposed (65). Such a hypothesis would be in keeping with the observation that an NPY antagonist was shown to be more potent in decreasing food intake in genetically obese Zucker (fa/fa) rats than in their lean littermates (66).
In summary, the present study shows that the peripheral administration of a melanocortin agonist, MTII, whatever its intimate mechanism, not only decreases food intake and body weight in lean and genetically obese Zucker (fa/fa) rats but also influences peripheral metabolism as well. It favors FFA utilization and up-regulates the expression of UCPs in BAT and muscles, that of an enzyme involved in lipid oxidation in the liver and WAT, CPT-1. Such effects are more marked in obese than lean animals, possibly because of the higher MC4 receptor density observed in these animals as a potential result of lowered endogenous melanocortin tone. Finally, the effects obtained with MTII in obese animals indicate that the melanocortin agonist adequately bypasses the leptin receptor defect, suggesting that the melanocortin pathway could be aimed at therapeutically in obesity syndromes associated with leptin resistance.
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Acknowledgments |
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Footnotes |
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Abbreviations: BAT, Brown adipose tissue; CPT, carnitine palmitoyl-transferase; G3PDH, glycerol-3-phosphate dehydrogenase; icv, intracerebroventricular; MTII, melanotan-II; UCP, uncoupling protein; WAT, white adipose tissue.
Received December 18, 2001.
Accepted for publication February 26, 2002.
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