The melanocortin-4 receptor (MC4R) is a well-validated drug target for the development of therapeutics for the treatment of obesity and disease cachexia. More recent studies suggest potential applications for MC4R compounds in diabetes and aspects of metabolic syndrome, depression related anorexia and anhedonia, and obsessive compulsive disorder. Clinical trials for treatment of common obesity using potent orthosteric agonists of the MC4R have failed, however, due to unacceptable target-mediated pressor activity. Two independent studies, however, have identified peptide MSH analogues that produce significant weight loss without a pressor response. Therefore, we hypothesize that the weight loss and pressor actions of MC4R can be discriminated pharmacologically, given a more thorough understanding of the mode(s) and site(s) of action of MC4R signaling in weight loss and cardiovascular regulation. During the previous funding period, we conducted a high throughput screen for positive allosteric modulators of the MC4R that identified a collection of 165 receptor-specific compounds in multiple mechanistic classes, and have demonstrated in vivo activity for several of these. Allosteric modulators of the MC4R should be applicable to treatment of syndromic obesity through restoration of normal levels of receptor activity in melanocortin receptor haploinsufficiency, a syndrome responsible for up to 5% of early onset obesity, and indeed a subset of our compounds are currently in the drug development pipeline at GSK. However, allosteric modulators of GPCRs, known to often exhibit excellent receptor subtype, ligand, and signaling mode specificity, are also outstanding tools for probing receptor function. We have also made significant progress in the identification of differentiated modes of MC4R signaling in vivo. During the previous funding period, we identified two novel signaling modalities of the receptor, melanocortin receptor associated protein 2 (MRAP2) mediated receptor-sensitization, and coupling of the receptor to an inwardly-rectifying K channel, Kir7.1 that is essential for depolarization of hypothalamic MC4R neurons by ?-MSH. In this application, we propose to use the unique pharmacological tools described above, and a set of tissue-specific knockout mice that delete G?s, Kir7.1, MRAP2, and ?-arrestin1 signaling in MC4R neurons to test the hypothesis that MC4R PAMS can correct melanocortin haploinsufficiency, and to identify the mode(s) and site(s) of action of MC4R in mediating its well-characterized weight loss, pressor, and cardioacceleratory effects. The results of this research program should 1) advance our understanding of the unique pharmacological properties of the MC4R, 2) enhance our understanding of the central control of energy homeostasis, 3) provide a unique set of pharmacological and genetic tools for the research community, and 4) provide the basic knowledge necessary to effectively utilize the MC4R as a drug target.

Public Health Relevance

The melanocortin-4 receptor (MC4R) is a well-validated drug target for the development of therapeutics for the treatment of obesity and disease cachexia, but clinical trials for obesity using potent orthosteric agonists of the MC4R have failed due to unacceptable target-mediated pressor activity. Data strongly suggests that these actions of the MC4R can be discriminated pharmacologically. Using a unique set of genetic tools, and a collection of small molecule allosteric modulators of the MC4R developed by this laboratory, we will identify the site(s) and mode(s) of action of the MC4R in weight loss and pressor activity, to learn how to effectively utilize the MC4R as a drug target.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK070332-11
Application #
8693457
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Pawlyk, Aaron
Project Start
2004-05-01
Project End
2018-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
11
Fiscal Year
2014
Total Cost
$673,959
Indirect Cost
$244,012
Name
Vanderbilt University Medical Center
Department
Physiology
Type
Schools of Medicine
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Lippert, Rachel N; Ellacott, Kate L J; Cone, Roger D (2014) Gender-specific roles for the melanocortin-3 receptor in the regulation of the mesolimbic dopamine system in mice. Endocrinology 155:1718-27
Panaro, Brandon L; Tough, Iain R; Engelstoft, Maja S et al. (2014) The melanocortin-4 receptor is expressed in enteroendocrine L cells and regulates the release of peptide YY and glucagon-like peptide 1 in vivo. Cell Metab 20:1018-29
Panaro, Brandon L; Cone, Roger D (2013) Melanocortin-4 receptor mutations paradoxically reduce preference for palatable foods. Proc Natl Acad Sci U S A 110:7050-5
Sebag, Julien A; Zhang, Chao; Hinkle, Patricia M et al. (2013) Developmental control of the melanocortin-4 receptor by MRAP2 proteins in zebrafish. Science 341:278-81
Srisai, Dollada; Gillum, Matthew P; Panaro, Brandon L et al. (2011) Characterization of the hyperphagic response to dietary fat in the MC4R knockout mouse. Endocrinology 152:890-902
Cone, Roger D; Simerly, Richard B (2011) Leptin grows up and gets a neural network. Neuron 71:4-6
Ghamari-Langroudi, Masoud; Cone, Roger D (2011) Shining a light on energy homeostasis. Cell Metab 13:235-6
Pantel, Jacques; Williams, Savannah Y; Mi, Dehui et al. (2011) Development of a high throughput screen for allosteric modulators of melanocortin-4 receptor signaling using a real time cAMP assay. Eur J Pharmacol 660:139-47
Ghamari-Langroudi, Masoud; Srisai, Dollada; Cone, Roger D (2011) Multinodal regulation of the arcuate/paraventricular nucleus circuit by leptin. Proc Natl Acad Sci U S A 108:355-60
Gruber, Kenneth A; Fan, Wei; Akerberg, Helena et al. (2009) Neuropeptide Y and gamma-melanocyte stimulating hormone (gamma-MSH) share a common pressor mechanism of action. Endocrine 35:312-24

Showing the most recent 10 out of 14 publications