Assessment of a small molecule melanocortin-4 receptor-specific agonist on energy homeostasis

David Cepoi; Teresa Phillips; Mary Cismowski; Val S. Goodfellow; Nick Ling; Roger D. Cone; Wei Fan

doi:10.1016/j.brainres.2003.10.041

Assessment of a small molecule melanocortin-4 receptor-specific agonist on energy homeostasis

David Cepoi
, Teresa Phillips
, Mary Cismowski
, Val S. Goodfellow
, Nick Ling
, Roger D. Cone
, Wei Fan

Pathology

Research output: Contribution to journal › Article › peer-review

32 Scopus citations

Abstract

The central melanocortin system has been demonstrated to play an important role in regulating different aspects of energy homeostasis. Understanding the specific contributions of MC3 and MC4 receptors, however, requires specific agonists and antagonists for each of the predominant forms of brain melanocortin receptors, MC3-R and MC4-R. We report here the characterization of a small peptide mimetic MC4-R-specific agonist that possesses both high affinity (K_i=11.3 nM) and potency (EC₅₀=1.62 nM) in vitro and is capable of inhibiting feeding behavior in mice when administered intracerebroventricularly (icv). Depending on the paradigm, acute (1 h following an overnight fast) or long-term (greater than 6 h under normal nocturnal feeding conditions) feeding inhibition was observed following icv injection. No effect on long-term feeding inhibition was observed with this compound in MC4-R knockout mice, and central administration of this compound had no effect on either metabolic rate or insulin release.

Original language	English (US)
Pages (from-to)	64-71
Number of pages	8
Journal	Brain Research
Volume	1000
Issue number	1-2
DOIs	https://doi.org/10.1016/j.brainres.2003.10.041
State	Published - Mar 12 2004

Funding

The authors thank Victor Hruby for peptides and Heather Takahashi for help preparing the manuscript. This work was supported by NIH AR42415.

Funders	Funder number
Author National Institutes of Health National Institutes of Health National Institutes of Health National Institutes of Health The Bev Hartig Huntington's Disease Foundation National Institutes of Health
National Institute for Arthritis and Musculoskeletal and Skin Diseases	R01AR042415

Keywords

Feeding
Ingestive behaviors
Melanocortin receptor
Neural basis of behavior
Obesity
POMC
Small molecule agonist

ASJC Scopus subject areas

General Neuroscience
Molecular Biology
Clinical Neurology
Developmental Biology

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10.1016/j.brainres.2003.10.041

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title = "Assessment of a small molecule melanocortin-4 receptor-specific agonist on energy homeostasis",

abstract = "The central melanocortin system has been demonstrated to play an important role in regulating different aspects of energy homeostasis. Understanding the specific contributions of MC3 and MC4 receptors, however, requires specific agonists and antagonists for each of the predominant forms of brain melanocortin receptors, MC3-R and MC4-R. We report here the characterization of a small peptide mimetic MC4-R-specific agonist that possesses both high affinity (Ki=11.3 nM) and potency (EC50=1.62 nM) in vitro and is capable of inhibiting feeding behavior in mice when administered intracerebroventricularly (icv). Depending on the paradigm, acute (1 h following an overnight fast) or long-term (greater than 6 h under normal nocturnal feeding conditions) feeding inhibition was observed following icv injection. No effect on long-term feeding inhibition was observed with this compound in MC4-R knockout mice, and central administration of this compound had no effect on either metabolic rate or insulin release.",

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author = "David Cepoi and Teresa Phillips and Mary Cismowski and Goodfellow, \{Val S.\} and Nick Ling and Cone, \{Roger D.\} and Wei Fan",

note = "Funding Information: The authors thank Victor Hruby for peptides and Heather Takahashi for help preparing the manuscript. This work was supported by NIH AR42415. ",

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AU - Cismowski, Mary

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AU - Ling, Nick

AU - Cone, Roger D.

AU - Fan, Wei

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N2 - The central melanocortin system has been demonstrated to play an important role in regulating different aspects of energy homeostasis. Understanding the specific contributions of MC3 and MC4 receptors, however, requires specific agonists and antagonists for each of the predominant forms of brain melanocortin receptors, MC3-R and MC4-R. We report here the characterization of a small peptide mimetic MC4-R-specific agonist that possesses both high affinity (Ki=11.3 nM) and potency (EC50=1.62 nM) in vitro and is capable of inhibiting feeding behavior in mice when administered intracerebroventricularly (icv). Depending on the paradigm, acute (1 h following an overnight fast) or long-term (greater than 6 h under normal nocturnal feeding conditions) feeding inhibition was observed following icv injection. No effect on long-term feeding inhibition was observed with this compound in MC4-R knockout mice, and central administration of this compound had no effect on either metabolic rate or insulin release.

AB - The central melanocortin system has been demonstrated to play an important role in regulating different aspects of energy homeostasis. Understanding the specific contributions of MC3 and MC4 receptors, however, requires specific agonists and antagonists for each of the predominant forms of brain melanocortin receptors, MC3-R and MC4-R. We report here the characterization of a small peptide mimetic MC4-R-specific agonist that possesses both high affinity (Ki=11.3 nM) and potency (EC50=1.62 nM) in vitro and is capable of inhibiting feeding behavior in mice when administered intracerebroventricularly (icv). Depending on the paradigm, acute (1 h following an overnight fast) or long-term (greater than 6 h under normal nocturnal feeding conditions) feeding inhibition was observed following icv injection. No effect on long-term feeding inhibition was observed with this compound in MC4-R knockout mice, and central administration of this compound had no effect on either metabolic rate or insulin release.

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KW - Melanocortin receptor

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KW - Obesity

KW - POMC

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Assessment of a small molecule melanocortin-4 receptor-specific agonist on energy homeostasis

Abstract

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Keywords

ASJC Scopus subject areas

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