Long term orexigenic effect of a novel melanocortin 4 receptor selective antagonist

Skúladóttir, Gudrún V.; Jónsson, Logi; Skarphedinsson, J. O.; Mutulis, Felikss; Muceniece, Ruta; Raine, Amanda; Mutule, Ilze; Helgason, Johannes; Prūsis, Peteris; Wikberg, Jarl E. S.; Schiöth, Helgi B.

doi:10.1038/sj.bjp.0702264

Cited by 74 publications

(43 citation statements)

References 30 publications

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“…The control rats were affected by the surgical operation associated with implantation of the osmotic pumps as indicated by a modest reduction in food intake and weight loss during the first week of treatment. The reduced food intake caused by the operation was blocked by the selective MC4 antagonist HS024, which is in agreement with earlier data from a 1-week study on HS028 (Skuladottir et al 1999) and a 2-week study on HS014 (Kask et al 1999), both substances being MC4 antagonists. This is also in agreement with previous results showing that immobilisation-induced anorexia was reversed by administration of the selective MC4 receptor antagonist HS014 (Vergoni et al 1999).…”

Section: Discussionsupporting

confidence: 81%

“…The peptides were dissolved in ACSF and infused at 0·25 µl/h. The selection of drug infusion rate (0·1 nmol/h) was based on previous experience (Haynes et al 1999, Kask et al 1999, Skuladottir et al 1999. The infusions were made with an osmotic minipump (Alzet, model 2004; Alza Corp., Palo Alto, CA, USA) which had first been activated by immersion in 0·9% saline at room temperature for 12 h before implantation.…”

Section: Implantation Of Pumpsmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 81%

Section: Implantation Of Pumpsmentioning

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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“…Tachyphylaxis to HS028 did not occur. However, neither energy expenditure nor pituitary function were examined in this study (17). Previous results from this department have demonstrated that AGRP (83-132), the endogenous hypothalamic melanocortin receptor antagonist, significantly increased 24-h food intake and antagonized the anorectic effects of ␣-MSH (16).…”

mentioning

confidence: 84%

Effects of Chronic Central Nervous System Administration of Agouti-Related Protein in Pair-Fed Animals

Small

Kim²,

Stanley³

et al. 2001

Diabetes

146

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The melanocortin receptor (MC3-R and MC4-R) antagonist, agouti-related protein (AGRP), is a potent stimulant of food intake. We examined the effect of chronic intracerebroventricular (ICV) AGRP treatment on energy metabolism and pituitary function in ad libitum fed rats and rats administered AGRP and then pair-fed to a saline control group. Chronic ICV AGRP (83-132) administration (1 nmol/day for 7 days) significantly increased food intake and body weight in ad libitum fed animals compared with saline-treated controls (body weight on day 7: 272 ± 6 [saline] vs. 319 ± 8 g [AGRP ad libitum fed]; P < 0.001). A significant increase in the epididymal fat pad weight, interscapular brown adipose tissue (BAT) weight, and plasma leptin was also observed in the ad libitum fed group. In the AGRP pair-fed group, a significant increase in the epididymal fat pad weight, BAT weight, and plasma leptin was again observed, suggesting that AGRP caused metabolic changes independent of increased food intake. BAT uncoupling protein 1 (UCP-1) content was significantly decreased compared with saline controls in both the AGRP ad libitum fed (21 ± 8% of saline control; P < 0.01) and AGRP pair-fed groups (24 ± 7% of saline control; P < 0.01). Plasma thyroid-stimulating hormone (TSH) was significantly suppressed compared with saline controls in both the AGRP ad libitum fed and AGRP pair-fed groups (3. T he hypothalamic melanocortin system is a regulator of energy homeostasis. The agouti-related protein (AGRP), produced in the arcuate nucleus, is an antagonist at the melanocortin 3 and 4 receptors (MC3-R and MC4-R), which are distributed throughout the brain. The proopiomelanocortin (POMC) products, such as ␣-melanocyte-stimulating hormone (␣-MSH), act as agonists at the melanocortin receptors (1-3). Hypothalamic POMC mRNA, AGRP mRNA, and the density of MC4-R have been shown to be altered with nutritional status (4,5). Defects of POMC processing and mutations of MC4-R in humans and mice are associated with gross obesity (6-11).5Administration of the synthetic MC3/4-R agonist MT II into the forebrain ventricles or directly into the paraventricular nucleus (PVN) of the hypothalamus of rats or mice produced a dosage-dependent reduction in food intake and body weight (12)(13)(14). A single injection of either the endogenous (AGRP ) or the synthetic (SHU9119 and HS014) MC3/4-R antagonists stimulated food intake in rodents (12,13,15,16). Chronic administration of the more selective MC4-R antagonist, HS028, for 7 days via an osmotic minipump significantly increased food intake and body weight. Tachyphylaxis to HS028 did not occur. However, neither energy expenditure nor pituitary function were examined in this study (17). Previous results from this department have demonstrated that AGRP (83-132), the endogenous hypothalamic melanocortin receptor antagonist, significantly increased 24-h food intake and antagonized the anorectic effects of ␣-MSH (16).The melanocortin system also influences energy expenditure. Intracerebroventricular (ICV) administra...

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“…A prominent role for the MC 4 R was highlighted by MC 4 R knockout mice, which exhibited maturity-onset obesity, overeating, hyperinsulinemia, and increased linear growth (Huszar et al 1997). The role of the MC 4 R in body weight regulation was further confirmed by pharmacologic studies showing that MC 4 R agonists suppress food intake and antagonists increase food intake (Kask et al 1998a;Murphy et al 1998;Skuladottir et al 1999). These studies led ultimately to the discovery of mutations in the melanocortin system in obese humans (Krude et al 1998).…”

Section: Animal Models Of Obesitymentioning

confidence: 99%

Relevance of animal models to human eating disorders and obesity

2008

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Background and rationale This review addresses the role animal models play in contributing to our knowledge about the eating disorders anorexia nervosa (AN) and bulimia nervosa (BN) and obesity. Objectives Explore the usefulness of animal models in complex biobehavioral familial conditions, such as AN, BN, and obesity, that involve interactions among genetic, physiologic, psychological, and cultural factors. Results and conclusionsThe most promising animal model to mimic AN is the activity-based anorexia rodent model leading to pathological weight loss. The paradigm incorporates reward elements of the drive for activity in the presence of an appetite and allows the use of genetically modified animals. For BN, the sham-feeding preparation in rodents equipped with a gastric fistula appears to be best suited to reproduce the postprandial emesis and the defects in satiety. Animal models that incorporate genes linked to behavior and mood may clarify biobehavioral processes underlying AN and BN. By contrast, a relative abundance of animal models has contributed to our understanding of human obesity. Both environmental and genetic determinants of obesity have been modeled in rodents. Here, we consider single gene mutant obesity models, along with models of obesigenic environmental conditions. The contributions of animal models to obesity research are illustrated by their utility for identifying genes linked to human obesity, for elucidating the pathways that regulate body weight and for the identification of potential therapeutic targets. The utility of these models may be further improved by exploring the impact of experimental manipulations on the behavioral determinants of energy balance.

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Long term orexigenic effect of a novel melanocortin 4 receptor selective antagonist

Cited by 74 publications

References 30 publications

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

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

Effects of Chronic Central Nervous System Administration of Agouti-Related Protein in Pair-Fed Animals

Relevance of animal models to human eating disorders and obesity

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