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Institute of Animal Science, Agricultural Research Organization, Volcani Center, PO Box 6, Bet Dagan 50250, Israel
1 Department of Chemistry, University of Arizona, Tucson, Arizona 85721, USA
(Requests for offprints should be addressed to M Friedman-Einat; Email: einat{at}agri.huji.ac.il)
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Abstract |
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-MSH and ACTH, also revealed a general similarity between the strains. Under feeding conditions ad libitum, POMC mRNA levels were highly similar in chicks of both strains and this level was significantly reduced upon feed restriction. However, POMC mRNA down-regulation upon feed restriction was more pronounced in layers than in broilers. These results suggest: (i) a role for MC3/4R agonists in the control of appetite; (ii) that the physiological differences between broilers and layers are not related to unresponsiveness of broiler chickens to the satiety signal of MC3/4R ligands. Therefore, these findings suggest that artificial activation of this circuit in broiler chicks could help to accommodate with their agricultural shortcomings of overeating, fattening, and impaired reproduction. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-melanocyte-stimulating hormone (-MSH), is the major activator of MCRs. It is produced from the precursor pro-opiomelanocortin (POMC) protein primarily in the pituitary gland but also at additional sites, including the neurons of the arcuate nucleus of the hypothalamus. The POMC glycoprotein is cleaved by two kinds of endoproteases, the prohormone convertase 1 (PC1, also called PC3), which generates adrenocorticotropic hormone (ACTH) from POMC and the prohormone convertase 2 (PC2), which cleaves ACTH and other parts of POMC to produce -, ß-, and 
-MSHs. Among the MCRs, MC3R and MC4R are most closely related to the control of energy balance and knockout of these receptors induces overeating and obesity in mice (Huszar et al. 1997, Takeuchi & Takahashi 1999, Chen et al. 2000, Williams et al. 2000, Matsumura et al. 2003). Agonists of MC3/4Rs are highly anorexic and antagonists generate orexigenic effects (Kask & Schioth 2000, Schioth et al. 2003). In humans, mutations in MC4R are found in about 4% of the morbidly obese (Vaisse et al. 2000, Farooqi & O’Rahilly 2005). Importantly, in rodents, the melanocortin system has been shown to influence not only food intake but also the reproductive axis (Hohmann et al. 2000, Small et al. 2002, Schioth et al. 2003).
The two most important commercial strains of chickens provide an excellent model system for studying the melanocortin circuit in avians. About 70 years of extensive selective breeding of chickens for high meat yield (broilers) and efficient egg production (layers) have resulted in two dramatically different strains of obese and lean phenotypes respectively. In comparison with layers, broilers are characterized by a much higher food intake and growth rate (Hocking et al. 1997), faster embryo growth rate (Ohta et al. 2004, Sato et al. 2006) and have higher brain levels of dopamine and dihydroxyphenylacetic acid (Saito et al. 2004). In agreement with these results, broilers were also shown to have lower basal metabolic rate (Kuenzel & Kuenzel 1977), physical activity (Saito et al. 2004), and protein degradation rate (Saunderson & Leslie 1988). Broilers and layers were found to differ in their patterns of eating behavior (Bokkers & Koene 2003) and in their response to several orexigenic and anorexic peptides applied by i.c.v. injection at neonatal age. These peptides include glucagon-like peptide-1 (GLP-1) (Tachibana et al. 2006), GLP-1 antagonist exendin (5–39), cocaine- and amphetamine-regulated transcript (Tachibana et al. 2001) and BAGA receptor antagonists (Takagi et al. 2003). Despite these characterizations performed by i.c.v. injections to neonatal chicks, possible interaction between these circuits and their possible contribution to the observed phenotypes of broiler and layer chickens are not yet understood.
The obese phenotype characteristic of broiler strains, fully manifested after sexual maturation, has a major negative impact on the industry due to increased prevalence of mortality and poor reproductive results, manifested as low egg yield and fertility (Mench 2002, Hocking & Robertson 2005, Tolkamp et al. 2005). Therefore, a study of the molecular control mechanisms of energy balance using broiler and layer chickens as a model, is of high importance for agricultural research as well. Chicken homologs to the mammalian MCR and POMC genes have been cloned (Takeuchi et al. 1996, 1998, 1999, Gerets et al. 2000), and found to share significant sequence similarity with their mammalian counterparts. Among the POMC gene products, the putative chicken -MSH, composed of 13 amino acids, is identical to its human counterpart. The other peptides derived from the POMC pre-protein exhibit high sequence similarity as well (Takeuchi et al. 1999). There is also a similarity between the expression profiles of chicken POMC and MCR genes and those of their mammalian homologs, although in chicken there is more pronounced expression in the peripheral tissues (Ottaviani et al. 1997, Takeuchi & Takahashi 1998, Takeuchi et al. 1999, Gerets et al. 2000, Ling et al. 2004). Intracerebroventricular injection of MC3/4R agonists in neonatal chicks or ringdoves has been shown to significantly inhibit food intake (Kawakami et al. 2000, Tachibana et al. 2001, Strader et al. 2003), as well as neuropeptide Y-induced feeding when neuropeptide Y is given simultaneously (Kawakami et al. 2000). However, this is the first report describing the effect of peripherally administered MC3/4R agonist on chickens, a comparison between the two commercial chicken strains representing obese and lean phenotypes, and a comparative analysis of POMC gene expression in the hypothalamus.
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Materials and Methods |
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MT-II, Ac-Nle-c[Asp5,DPhe7,Lys10]-alpha-MSH(4–10)-NH2, a cyclic heptapeptide analog of -MSH, has been discovered in V Hruby’s laboratory to be a highly potent MCR agonist (Al–Obeidi et al. 1989a, 1989b, Haskell-Luevano et al. 1994, Schioth et al. 1997, Yang et al. 1997). MT-II was prepared using solid-phase chemistry as described in the above-cited papers.
Animals
Day-old female white Leghorn (Lohman) chicks, representing layer chickens, and Cobb chicks, representing broiler chickens, were purchased from local husbandries (Hasolelim, Kibutz Hasolelim, Israel, and Brown, Hod Hasharon, Israel, respectively). Both chick types were raised in battery brooders. One week before the experiments they were moved into cages with two chicks per cage, and one day before the experiment they were moved to individual cages. Commercial diets (layer diet for layers and broiler diet for broilers) and water were supplied ad libitum, unless otherwise noted. Photo schedule was of a ratio of 14 h light:10 h darkness, but following MT-II injections light was kept for 24 h per day. Chicks were cared for under the guidelines of the Animal Experimentation Committee, ARO, the Volcani Center.
Feed restriction
At 15 days of age, chicks of both strains were given 70% of their food consumption fed ad libitum. After 4 days, the feed restricted chicks from each strain were divided into two groups according to similar body weights (BWs) and minimal variance of BW within groups (n=6). For the analysis of POMC mRNA, 3-week-old broiler and layer chicks were divided into two groups as described above (n=4). Feed restriction was performed similarly to that described above but allowing only 50% of their food consumption fed ad libitum. Feed restriction was for 7 days.
Injection of MT-II
Intravenous injection into the wing vein was performed with either 0.2 ml PBS (control group) or 0.2 ml PBS containing 1 mg/kg BW MT-II (treated group). After injection, chicks were allowed to feed ad libitum. Food consumption, water consumption and BW were measured every hour for the first 8 h and every 24 h thereafter.
mRNA analysis
Total RNA was isolated from the hypothalamus as described previously (Horev et al. 2000). Each sample was pooled from four birds. RNA samples (20 µg/lane) were separated on a 1.2% agarose/2.2 M formaldehyde gel and blotted onto a nylon membrane (Nytran N, Schleicher & Schuell, Tamar, Jerusalem, IL) according to standard procedures (Sambrook & Russell 2001). POMC probe was prepared by reverse transcriptase (RT)-PCR using hypothalamic mRNA from layer chicks as template; forward primer: 5'-agcggcccatgctgggagaac-3' and reverse primer: 5'-ctgacccttcttgtaggcgct-3'. The resulting product was verified by sequencing. Labeling with [32]P-deoxycytidine-triphosphate was carried out with the random priming kit from Roche Diagnostics (Dyn Diagnostics, Keysaria, IL, USA) and specific activity was 1 x 108 cpm/mg DNA. Prehybridization and hybridization at 42 ° C, and washing under high-stringency conditions were performed according to Sambrook and Russell (2001). Membranes were then exposed to x-ray film (Kodak) using a TransScreen-HE intensifying screen (Kodak). Band intensity was calculated with the NIH ImageJ program (Bethesda, MD, USA).
Statistical analysis
All data are expressed as means ± S.E.M. Data were analyzed using the Student’s t-test. Statistics was performed using SAS software (Cary, NC, USA), and a two-tailed significance level of P < 0.05.
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Results |
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The direct effect of the synthetic MT-II agonist of MC3/4Rs on food intake of broiler and layer chicks was studied following i.v. injection of MT-II (1 mg/kg BW) to 19-day-old chicks. Food intake following a single administration of MT-II or vehicle (PBS) into the wing vein is shown in Fig. 1A and B
. Injection was administered 4 days after feed restriction to 70% of food consumption ad libitum. This feed restriction explains the high food consumption observed for the control groups of both strains of chicks injected with vehicle alone. Despite this feed restriction, during the first hour post injection, the MT-II-treated broilers and layers ate about one-third the amount of food eaten by their corresponding control groups (28 and 33% for broiler and layer chicks respectively).
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) demonstrate that the treated layers had already matched the cumulative food intake of their control counterparts by 5 h post injection, whereas the treated broilers matched their controls some time between 8 and 24 h after injection. A comparison of the satiety effect of the MT-II treatment on broiler and layer chicks is shown in Fig. 2, where the cumulative food intake of each strain is normalized to their daily food intake. The normalized values show a very strong similarity in the responses of the treated broilers and layers during the first 8 h post injection. It is striking that the biggest difference between the strains lies in the response of their control groups to the feed restriction, which occurred prior to injection, while the response to MT-II treatment was highly similar.
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) is more complicated, since it reflects not only the real increase in BW but also food accumulation in the crop and the effect of drinking, which increases with elevated food intake (Fig. 4). Nevertheless, the general patterns of cumulative BW shown in Fig. 3 are similar to those of the cumulative food intake (Fig. 1C and D). The main difference is the noticeable reduction in the cumulative BW of layers between 8 and 24 h. This reduction reflects the fact that much of the BW gain during the first hour post exposure to feeding ad libitum evolved from the accumulation of undigested food and water in the crop. However, since feed-conversion efficiencies are higher in broilers compared with layers (Marks 1980, Leenstra & Pit 1988, Morris & Njuru 1990, Gilbert et al. 1999, MacLeod et al. 1999) the reduced BW due to ingestion of the stored food is less pronounced in broilers. Moreover, the higher rate of food intake of the broiler chicks further masked the expected reduction in their apparent BW.
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), obtained by dividing the cumulative BW values by the initial BW of each chick (Fig. 3C), shows that using this criterion as well, treated and control layers reached a similar mean relative BW by 6 h post injection, whereas broiler chicks did the same only between 8 and 24 h post injection. This experiment was repeated a few times using younger (one week of age) and older (4 months of age) hens of both genders and similar results were obtained (not shown). Administration of twofold lower amounts of MT-II did not elicit a response in either broiler or layer chicks (not shown).
Expression analysis of POMC mRNA
As both strains of chicks responded similarly to the exogenous -MSH agonist, we compared the expression of the endogenous POMC gene, which codes for -MSH and other melanocortin peptides in the hypothalamus of the two strains. As shown in Fig. 5, similar levels of POMC mRNA were deserved in the hypothalamus of the two strains. This POMC expression level decreased significantly in chicks of both strains after 7 days of feed restriction (FR broilers and layers). The level of POMC expression in the hypothalamus of feed-restricted layer chicks was lower than that in broiler chicks (12 and 40% relative to the level obtained in broilers fed ad libitum) (Fig. 5C).
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Discussion |
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Despite their apparently low sensitivity to satiety signals and their extreme levels of food consumption, broiler chicks were no less sensitive than layer chicks to the attenuation of food intake induced by MT-II treatment. Considering the effective time period of the treatment, broilers seemed to be even more sensitive than layers, since it took them longer to match the amounts of food consumption and BWs of their control counterparts. It could be argued, however, that this difference stems from their inherently higher food consumption mediated through additional signaling circuits, rather than from different sensitivity to the MT-II treatment. This higher tendency of food intake imposes a longer period of time for the treated broiler chicks to match up the amount of food intake to that of their control chicks. This effect of MT-II treatment on food intake was confirmed by our study of BW. However, one should take into account that much of the increase in BW in the first few hours post exposure to feeding ad libitum was due to food accumulation in the crop. At longer time periods, when the contribution of food stores to the measurement of cumulative BW is reduced, the measurements of cumulative BW revealed that after 24 and 5 h for broiler and layers respectively, no significant differences in BW could be observed between the treated and control groups of each strain. At the same time periods, cumulative food intake also equalized between each of the treated groups and its respective control. This could serve as an indirect indication that regardless of the MT-II treatment for each strain, a given amount of food intake resulted in a given amount of BW change, meaning that the MT-II treatment had no major effect on energy expenditure. However, since no direct measurement of energy expenditure was made, small transient effects of MT-II treatment on energy expenditure, which could be masked at longer period of times, cannot be ruled out.
The general finding that broiler chicks were not less sensitive than layer chicks in their responsiveness to the satiety signal of the -MSH analog agrees with the findings in rodents. In all genetically and experimentally obese rodent models (except those mutated in MC4R; Marsh et al. 1999), MT-II has been shown to be as effective in attenuating food intake as in control mice (Fan et al. 1997, Hohmann et al. 2000, Pierroz et al. 2002). Moreover, consistent with our finding of a longer period of MT-II effectiveness in broilers, similar results were reported in a model of obesity in rats, in which a longer persistence of the anorectic effect of MT-II treatment was observed in leptin-induced, leptin-resistant rats compared with control lean rats (Scarpace et al. 2003).
The concern about a possible aversive effect of the MT-II treatment is based on a previous publication in rats (Benoit et al. 2003) and 21% of MT-II treated humans (Wessells et al. 2000). However, data accumulated from studies in mammals indicate that the effects of MT-II on food intake and BW are specific. Examples are the report by Seeley et al.(2005) demonstrating that the effects of chronic s.c. infusion of MT-II on food intake are secondary to regulation of body weight and adiposity, and a report by Benoit et al.(2000), where another MC4R agonist (Ro27–3225, clearly non-aversive), imposed similar effects to those of MT-II. For chicken, nothing is known regarding the possibility of aversive effects of MT-II, but taking into account the inspected normal behavior of the treated chicks, the similarity of MT-II effects in the chicks with those following i.c.v. injection to ring dove (Strader et al. 2003) and those reported in mammals, suggests that the MT-II effects on the broiler and layer chicks reported here are specific.
For both rodents and birds, the similarity of the effects obtained by i.c.v. injection and peripheral injection (at much higher amounts when calculated as micrograms per animal), suggests that the main site of action of MT-II is the brain (Murphy et al. 2000, Azzara et al. 2002, Moran et al. 2002, Pierroz et al. 2002, Bellinger et al. 2003, Choi et al. 2003, Hansen et al. 2005), but some contradictory results in rodent suggested that MT-II does not cross the blood–brain barrier (Trivedi et al. 2003). Taking this into account and the wide peripheral tissue specificity of expression of MC3R and MC4R in chickens (Takeuchi & Takahashi 1998, 1999), we cannot exclude the possibility that the injected MT-II operated through peripheral receptors.
Although MT-II is a non-selective agonist of MCRs, its effect on feeding, at least in rodents, is mainly mediated by MC4R. This was clearly demonstrated with MC4R-deficient mice (Huszar et al. 1997). MT-II administration in these mice, applied either i.c.v. or peripherally, had no detectable effect on food intake (Marsh et al. 1999, Chen et al. 2000), while strongly attenuating food intake in the normal control mice. The chicken MC4R, sharing on average, 87% identity with its mammalian homologs, has been cloned (Takeuchi & Takahashi 1998). Initial characterization of MC4R’s expression pattern by RT-PCR showed a similarity in expression in the brain, but a wider range of peripheral expression compared with mammals (Takeuchi & Takahashi 1998).
The high affinity of the synthetic MT-II to chicken MCRs was demonstrated by the use of MCR-transfected cells in culture (Ling et al. 2004). By expressing each of the chicken MCR cDNAs in HEK-293 cells, these authors demonstrated a very high potency of MT-II and human ACTH for the activation of the chicken MC3R and MC4R, whereas -MSH was much less effective in these experiments. Since the human and chicken ACTH sequences differ by only two substitutions, it seems logical to assume that similar results would be obtained also with the chicken-derived ACTH, therefore suggesting that in chickens, ACTH, rather than -MSH, is the primary natural agonist of the MC4R receptor. This hypothesis is also compatible with the fact that in chickens, the intermediate lobe, which is the major source of -MSH in other vertebrates, is not well developed and with the suggestion that -MSH in chickens operates in autocrine and paracrine rather than endocrine circuits (Takeuchi et al. 2003, Boswell & Takeuchi 2005).
In humans, mutations in the MC4R appear to be the most common monogenic cause of obesity known today accounting for about 5% of the morbidly obese population (Farooqi et al. 2000). The similarity between broiler and layer chicks with respect to their response to MT-II injection suggests that the obese phenotype of the broiler strain does not stem from impaired MC4R signaling. Therefore, these receptor agonists are potential future agents for the control of feeding in broiler breeder flocks. The recent finding of an orally active non-peptide antagonist of MC4R (Tucci et al. 2005) suggests the possibility of identifying a suitable agent that could be mixed with food and control feed intake in direct proportion to its consumption.
Expression studies of the POMC gene, encoding the precursor proteins of -MSH, ACTH, and several other peptides in the hypothalamus, showed a high degree of similarity between broilers and layers. A relatively high level of mRNA expression was observed in both strains under conditions of being fed ad libitum, followed by a markedly reduced level after 1 week of feed restriction. Given that a much higher fat content is typical to broiler chicks even at this young age (Griffin et al. 1991), and assuming that adipose-secreted proteins elicit brain response in chickens (Horev et al. 2000, Ohkubo et al. 2000) similarly to that described for mammals (Ahima & Flier 2000, Saltiel 2001), a much higher hypothalamic POMC level would be expected under the assumption of similar sensitivity to these fat-secreted signals. Therefore, despite our results showing the higher fat content of the broiler chicks, the similarity of POMC steady-state levels in their hypothalamus to those of layer chicks suggests a lower sensitivity of broiler chicks to these satiety signals. It is logical to assume that control mechanisms operating upstream of POMC activation in response to satiety signals from peripheral tissues operate at a lower efficiency, possibly contributing to the obese phenotype of broiler breeders.
The stronger down-regulation of POMC mRNA expression observed in the layer hypothalamus correlates with the almost total lack of abdominal fat observed in these animals compared with the significant amount of fat tissue still present in the feed-restricted broilers (not shown). However, a more accurate means of mRNA quantization is required to confirm this observation.
The use of broiler and layer chickens, the two most important commercial strains, as a model system to study the physiological aspects of obesity is of high importance for both academic and agricultural research. In order to study the genetics of these traits, a number of laboratories have established their own selection procedure towards the generation of strains with more defined founder population and traits (such as high and low BW, abdominal fat, plasma very low density lipoprotein concentration, and fasting glycemia; Whitehead & Griffin 1984, Cahaner & Nitsan 1985, Simon & Leclercq 1985, Dunnington & Siegel 1996, Park et al. 2006). A striking phenomenon that appeared from these experimental breeding programs and from the commercial breeding programs is the non-exhausting genetic variation for these traits. This phenomenon, recently coined by Eitan & Soller (2004) as the "Selection Induced Genetic Variation" (SIGV), was especially evident in the long-term divergent selection for BW initiated in 1957 (Dunnington & Siegel 1996, Carlborg et al. 2006) as well as in the long-term commercial selection of broiler chickens. Recent quantitative trait loci analysis has identified four interacting loci comprising of more than 800 F2 bird progeny of reciprocal intercross between the long tern-selected lines with high and low BW (Jacobsson et al. 2005, Park et al. 2006). The authors suggested that interlocus interactions (epistasis) between these loci, along with the increasing proportion of beneficial allelic combinations for the selected trait, led to the release of new genetic variation with multiple synergistic interactions. This comprehensive QTL analysis and the use of an epistatic approach provided the first empirical support for explaining this phenomenon of SIGV, thus offering a classical Mendelian explanation for a seemingly Lamarckistic-type phenomenon.
The study on candidate gene function such as those of MC3/4R agonists described here may contribute to deciphering the high complexity of the control mechanism on energy balance in chickens. The importance of studying agonists of the MC3/4R is due not only to their affect on appetite and BW but also to their potential enhancing effect on the hypothalamus–pituitary–gonadal axis (Kim et al. 2000, Watanobe et al. 2001). Experiments involving prolonged treatments in chickens are therefore needed to assess the possible involvement of the melanocortin-receptor circuit in the regulation of obesity and reproduction.
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Acknowledgements |
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Funding |
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References |
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Received in final form 7 April 2006
Accepted 21 April 2006
Made available online as an Accepted Preprint 10 May 2006
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