Differential effects of melanocortin peptides on ingestive behaviour in rats: evidence against the involvement of MC3 receptor in the regulation of food intake

Kask, Ants; Rägo, Lembit; Wikberg, Jarl E. S.; Schiöth, Helgi B.

doi:10.1016/s0304-3940(00)00837-5

Cited by 61 publications

(45 citation statements)

References 19 publications

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“…These observations cast doubt on the assertion that MSH is the sole physiological MC4-R ligand. Interestingly, intracerebroventricular injection of ACTH, MSH and da-MSH, significantly reduce food intake in rodents with varying potencies (Abbott et al 2000, Kask et al 2000, Al-Barazanji et al 2001. These peptides, therefore, are likely to be important endogenous ligands in the central melanocortin system.…”

Section: Discussionmentioning

confidence: 99%

“…In vitro experiments have shown that some POMC-derived peptides, in addition to MSH, can bind and activate the MC4-R (Gantz et al 1993, Mountjoy et al 1994, Abbott et al 2000. Furthermore, in vivo experiments have indicated that several POMC-derived peptides can inhibit food intake with varying efficacies when injected intracerebroventrically (Abbott et al 2000, Kask et al 2000, Al-Barazanji et al 2001, Millington et al 2001. This suggests that several POMC-derived peptides are physiologically relevant in the melanocortin system.…”

Section: Introductionmentioning

confidence: 99%

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Agouti-related protein (83-132) is a competitive antagonist at the human melanocortin-4 receptor: no evidence for differential interactions with pro-opiomelanocortin-derived ligands

Pritchard

Armstrong²,

Davies³

et al. 2004

Journal of Endocrinology

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Interactions between pro-opiomelanocortin (POMC)-derived peptides, agouti-related protein (AGRP) and the melanocortin-4 receptor (MC4-R) are central to energy homeostasis. In this study we have undertaken comprehensive pharmacological analysis of these interactions using a CHOK1 cell line stably transfected with human MC4-R. Our main objectives were (1) to compare the relative affinities and potencies of POMC-derived peptides endogenously secreted within the hypothalamus, (2) to investigate the potency of AGRP(83-132) antagonism with respect to each POMC-derived peptide and (3) to determine whether AGRP(83-132) and POMC-derived peptides act allosterically or orthosterically. We have found that beta melanocyte-stimulating hormone ( MSH), desacetyl alpha MSH (da-MSH) and adrenocorticotrophic hormone all have very similar affinities and potencies at the MC4-R compared with the presumed natural ligand, MSH. Moreover, even MSH precursors, such as beta lipotrophic hormone, showed significant binding and functional activity. Therefore, many POMCderived peptides could have important roles in appetite regulation and it seems unlikely that MSH is the sole physiological ligand. We have shown that AGRP(83-132) acts as a competitive antagonist. There was no significant difference in the potency of inhibition by AGRP(83-132) or agouti(87-132) at the MC4-R, regardless of which POMC peptide was used as an agonist. Furthermore, we have found that AGRP(83-132) has no effect on the dissociation kinetics of radiolabelled Nle 4 ,D-Phe 7 MSH from the MC4-R, indicating an absence of allosteric effects. This provides strong pharmacological evidence that AGRP(83-132) acts orthosterically at the MC4-R to inhibit Gs-coupled accumulation of intracellular cAMP.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Agouti-related protein (83-132) is a competitive antagonist at the human melanocortin-4 receptor: no evidence for differential interactions with pro-opiomelanocortin-derived ligands

Pritchard

Armstrong²,

Davies³

et al. 2004

Journal of Endocrinology

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“…the MC3 and MC4 receptors (Fan et al 1997). It is, however, unlikely that MT-II influences food intake through the MC3 receptor as it has been shown that -MSH, a peptide with a preference for the MC3 receptor, does not influence food intake, while both -MSH and -MSH are effective (Kask et al 2000) and that the MC3 knock-out mice eat normally (Chen et al 2000). We have shown the peptides to be stable in ACSF for at least 4 weeks at 37 C. The recovery of food intake and body weight increase in the MT-II-treated rats after the first week of treatment is thus not likely to be due to degradation of the peptides.…”

Section: Discussionmentioning

confidence: 99%

Food conversion is transiently affected during 4-week chronic administration of melanocortin agonist and antagonist in rats

Jónsson

Skarphedinsson

Skúladóttir³

et al. 2002

Journal of Endocrinology

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The central melanocortin system is involved in the regulation of food intake and body weight. In this study, we investigated the effect of a 4-week intracerebroventricular infusion of the melanocortin receptor agonist MT-II and the selective melanocortin-4 receptor antagonist HS024 on food intake and body weight homeostasis. The MT-IItreated rats ate less and lost considerably more weight than the control rats during the first week of treatment. During the second and third week, they gained weight and, by the end of the treatment period, the weight gain was similar to that of the control rats. The HS024 treatment caused hyperphagia and development of obesity during the entire period. Extensive accumulations of fat and a sixfold increase in leptin levels were observed in the HS024-treated rats, as compared with controls, after the 4-week period. Food conversion ratio, defined as body weight increase relative to weight of ingested food, was clearly increased in the HS024-treated rats, while it was lowered in the MT-II-treated rats compared with controls. The effect on food conversion ratio was transient, being greatest for both experimental groups during the first week and it was then attenuated to reach the level of controls at the end of the study. The results suggest that long-term injection of exogenous melanocortin receptor active substances may have an important transient effect on food conversion.

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“…Blockade or absence of MC4R induces hyperphagia, reduced energy expenditure and obesity (Balthasar et al, 2005;Butler and Cone, 2003). Interestingly, MC4R are expressed not only in the hypothalamus but also in the amygdala (Mountjoy et al, 1994); melanocortin signaling in the CeA can indeed regulate feeding behavior bidirectionally, with MC4R exerting a tonic inhibitory role on feeding (ie, producing anorexia) (Boghossian et al, 2010;Kask et al, 2000a).…”

Section: Introductionmentioning

confidence: 99%

Pituitary Adenylate Cyclase-Activating Peptide in the Central Amygdala Causes Anorexia and Body Weight Loss via the Melanocortin and the TrkB Systems

Iemolo

Ferragud

Cottone

et al. 2015

Neuropsychopharmacol

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Growing evidence suggests that the pituitary adenylate cyclase-activating polypeptide (PACAP)/PAC1 receptor system represents one of the main regulators of the behavioral, endocrine, and autonomic responses to stress. Although induction of anorexia is a well-documented effect of PACAP, the central sites underlying this phenomenon are poorly understood. The present studies addressed this question by examining the neuroanatomical, behavioral, and pharmacological mechanisms mediating the anorexia produced by PACAP in the central nucleus of the amygdala (CeA), a limbic structure implicated in the emotional components of ingestive behavior. Male rats were microinfused with PACAP (0-1 μg per rat) into the CeA and home-cage food intake, body weight change, microstructural analysis of food intake, and locomotor activity were assessed. Intra-CeA (but not intra-basolateral amygdala) PACAP dose-dependently induced anorexia and body weight loss without affecting locomotor activity. PACAP-treated rats ate smaller meals of normal duration, revealing that PACAP slowed feeding within meals by decreasing the regularity and maintenance of feeding from pellet-to-pellet; postprandial satiety was unaffected. Intra-CeA PACAP-induced anorexia was blocked by coinfusion of either the melanocortin receptor 3/4 antagonist SHU 9119 or the tyrosine kinase B (TrKB) inhibitor k-252a, but not the CRF receptor antagonist D-Phe-CRF(12-41). These results indicate that the CeA is one of the brain areas through which the PACAP system promotes anorexia and that PACAP preferentially lessens the maintenance of feeding in rats, effects opposite to those of palatable food. We also demonstrate that PACAP in the CeA exerts its anorectic effects via local melanocortin and the TrKB systems, and independently from CRF.

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Differential effects of melanocortin peptides on ingestive behaviour in rats: evidence against the involvement of MC3 receptor in the regulation of food intake

Cited by 61 publications

References 19 publications

Agouti-related protein (83-132) is a competitive antagonist at the human melanocortin-4 receptor: no evidence for differential interactions with pro-opiomelanocortin-derived ligands

Agouti-related protein (83-132) is a competitive antagonist at the human melanocortin-4 receptor: no evidence for differential interactions with pro-opiomelanocortin-derived ligands

Food conversion is transiently affected during 4-week chronic administration of melanocortin agonist and antagonist in rats

Pituitary Adenylate Cyclase-Activating Peptide in the Central Amygdala Causes Anorexia and Body Weight Loss via the Melanocortin and the TrkB Systems

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