The regulation of food intake by selective stimulation of the type 3 melanocortin receptor (MC3R)

Marks, Daniel L.; Hruby, Victor J.; Brookhart, Gregor; Cone, Roger D.

doi:10.1016/j.peptides.2005.01.025

Cited by 103 publications

(98 citation statements)

References 32 publications

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“…PG946 is a moderately selective Mc3r antagonist [3]. Peripheral injections of an Mc3r agonist were recently reported to increase food intake, perhaps through regulation of neurons expressing the potent orexigens Neuropeptide Y and AgRP in the arcuate nucleus [26]. The Mc3r may also be involved in the stimulation of food intake by AgRP, which is an inverse agonist and antagonist at the Mc3r and Mc4r [29].…”

Section: Discussionmentioning

confidence: 99%

“…Analysis of Mc3r and Mc4r knockout mice indicate a minimal role for the Mc3r in regulating food intake [5]. However, recent data suggests that stimulation of MC3R by peripheral administration of a moderately selective agonist D-trp8-γMSH can increase food intake, perhaps through stimulation of neurons co-expressing NPY and AgRP [26].…”

Section: Introductionmentioning

confidence: 99%

“…The second peptide, PG946, is a cyclic α-MSH/β-MSH hybrid that is a selective Mc3r antagonist [3]. Since the peripheral administration of D-trp8-γMSH can increase food intake [26], we were interested in determining whether PG-932 administered peripherally would have an anorectic effect. We demonstrate herein that unlike SHU9119, PG932 dose-dependently increases food intake when administered peripherally, most likely through antagonism at Mc4r.…”

Section: Introductionmentioning

confidence: 99%

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A derivative of the melanocortin receptor antagonist SHU9119 (PG932) increases food intake when administered peripherally

Sutton

Babin

et al. 2008

Peptides

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Melanocortin receptors are considered promising candidates for the treatment of behavioral and metabolic disorders ranging from obesity to anorexia and cachexia. These experiments examined the response of mice to peripheral injections of two compounds. PG932 is a derivative of SHU9119 which is non-selective antagonist of melanocortin-3 and melanocortin-4 receptors (Mc3r, Mc4r). PG946 is a derivative of a hybrid of alpha-and beta-MSH, and is a moderately selective Mc3r antagonist. SHU9119 increases food intake when administered intracerebroventricularly but is without effect when injected into the periphery. In contrast, PG932 was found to be highly effective at stimulating food intake when administered peripherally by intraperitoneal injection. The orexigenic effect of PG932 required functional Mc4r, suggesting that inhibition of this receptor is involved in the stimulation of food intake. PG946 did not significantly affect on feeding behavior. PG932 is thus a useful new compound for studies examining the regulation of appetite and energy balance, and may also prove useful for the treatment of cachectic conditions.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A derivative of the melanocortin receptor antagonist SHU9119 (PG932) increases food intake when administered peripherally

Sutton

Babin

et al. 2008

Peptides

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“…MC3R is located in the brain where it is expressed in the hypothalamus (Marks et al 2006) especially in the arcuate nucleus (Roselli-Rehfuss et al 1993; Mountjoy et al 1994;Mountjoy & Wild 1998). MC3R knockout mice display reduced lean body mass, an increased fat mass and are slightly hypophagic compared to wild type controls (Marks et al 2006), but the receptor has not been ascribed lipolytic importance. MC4R is widely located throughout the CNS and high levels have been found especially in hypothalamic regions involved in regulation of feeding behaviour and energy expenditure, such as the paraventricular nucleus of the hypothalamus (Mountjoy et al 1994;Mountjoy & Wild 1998).…”

Section: Introductionmentioning

confidence: 99%

“…The receptor has by some researchers been identified in human subcutaneous WAT (Smith et al 2003), although the lipolytic function remains unclear. MC3R is located in the brain where it is expressed in the hypothalamus (Marks et al 2006) especially in the arcuate nucleus (Roselli-Rehfuss et al 1993;Mountjoy et al 1994;Mountjoy & Wild 1998). MC3R knockout mice display reduced lean body mass, an increased fat mass and are slightly hypophagic compared to wild type controls (Marks et al 2006), but the receptor has not been ascribed lipolytic importance.…”

Section: Introductionmentioning

confidence: 99%

Characterization of murine melanocortin receptors mediating adipocyte lipolysis and examination of signalling pathways involved

Møller

Raun

Jacobsen

et al. 2011

Molecular and Cellular Endocrinology

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The melanocortin receptors (MCRs) belong to the G-protein coupled receptors (family A). So far, 5 different subtypes have been described (MC1R-MC5R) and of these MC2R and MC5R have been proposed to act directly in adipocytes and regulate lipolysis in rodents. Using ACTH and -melanocyte stimulating hormone (-MSH) generated from proopiomelanocortin (POMC), as well as synthetic MSH-analogues to stimulate lipolysis in murine 3T3-L1 adipocytes it is shown that MC2R and MC5R are lipolytic mediators in differentiated 3T3-L1 adipocytes. Involvement of cAMP, phosphorylated extracellular signal-regulated kinase (ERK) 1/2, protein kinase B (PKB), adenosine 5' monophosphateactivated protein kinase (AMPK) and Jun-amino-terminal kinase (JNK) in MCR mediated lipolysis were studied. Interestingly, results obtained in 3T3-L1 cells suggest that lipolysis stimulated by -MSH, NDP--MSH, MT-II, SHU9119and PG-901 is mediated through MC5R in a cAMP independent manner. Finally, we identify essential differences in MCR mediated lipolysis when using 3T3-L1 cells compared to primary adipocytes. INTRODUCTIONThe melanocortin system acts through multiple pathways relevant for the prevention of obesity and obesity-related complications (Cone 1999;Marks et al. 2002;Spiegelman & Flier 2001). The system is acknowledged to have an important function in regulation of satiety and energy expenditure (Yaswen et al. 1999;Spiegelman & Flier 2001;Cheung et al. 1997;Azzara et al. 2002). MC4R knockout mice exhibit a well-described phenotype defined by increased lean body mass and fat mass, hyperphagia and disturbances in the metabolic response to overnutrition (Mountjoy et al. 1994;Huszar et al. 1997;Tschop & Heiman 2001). Furthermore, loss of MC4R function is the most frequent monogenetic alteration in severely obese humans (Krude et al. 1998) and in severe, early onset childhood obesity the frequency of mutations in the MC4R locus is 4-6% (Farooqi et al. 2003). Besides the effect on satiety and energy expenditure, the melanocortin system is believed to influence insulin release and insulin sensitivity (Fan et al. 2000;Huo et al. 2009). The melanocortin peptides and their receptors are also suspected to have a direct lipolytic effect on adipose tissues in rodents (Cho et al. 2005;Boston 1999;Spirovski et al. 1975). However this effect is controversial in humans (Hoch et al. 2007). The effect of melanocortins on adipocytes have by some researchers been explained by neuronal regulation of lipolysis (Brito et al. 2007), since MC4R mRNA has been identified in sympathetic neurons connected to white adipose tissue (WAT), indicating that central MC4R might stimulate lipid mobilization in the periphery (Song et al. 2005). However, studies in differentiated murine 3T3-L1 adipocytes suggest a direct lipolytic effect stimulated by melanocortin peptides ACTH and -MSH (Bradley et al. 2005;Cho et al. 2005), Page 3 of 24 A c c e p t e d M a n u s c r i p t 3 which supports the earlier identification of MC2R and MC5R mRNA in this cell line (Boston & Cone 1996). MC1R...

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A proopiomelanocortin‐derived peptide sequence enhances plasma stability of peptide drugs

2020

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Bioactive peptide drugs hold promise for therapeutic application due to their high potency and selectivity but display short plasma half‐life. Examination of selected naturally occurring peptide hormones derived from proteolytic cleavage of the proopiomelanocortin (POMC) precursor lead to the identification of significant plasma‐stabilizing properties of a 12‐amino acid serine‐rich orphan sequence NSSSSGSSGAGQ in human γ3‐melanocyte‐stimulating hormone (MSH) that is homologous to previously discovered NSnGGH (n = 4–24) sequences in owls. Notably, transfer of this sequence to des‐acetyl‐α‐MSH and the therapeutically relevant peptide hormones neurotensin and glucagon‐like peptide‐1 likewise enhance their plasma stability without affecting receptor signaling. The stabilizing effect of the sequence module is independent of plasma components, suggesting a direct effect in cis. This natural sequence module may provide a possible strategy to enhance plasma stability, complementing existing methods of chemical modification.

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The regulation of food intake by selective stimulation of the type 3 melanocortin receptor (MC3R)

Cited by 103 publications

References 32 publications

A derivative of the melanocortin receptor antagonist SHU9119 (PG932) increases food intake when administered peripherally

A derivative of the melanocortin receptor antagonist SHU9119 (PG932) increases food intake when administered peripherally

Characterization of murine melanocortin receptors mediating adipocyte lipolysis and examination of signalling pathways involved

A proopiomelanocortin‐derived peptide sequence enhances plasma stability of peptide drugs

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