Obesity (body mass index, BMI >30) afflicts millions of people in the United States (an estimated 97 million adults in the U.S.) and other countries, and is a major risk factor for heart disease, type II diabetes mellitus, stroke, hypertension, and morbidity. In industrialized countries, the problem of obesity is compounded by overeating, a high fat content diet, and a lack of exercise. The last few years have seen the characterization of over 30 neuroendocrine pathways that have been identified to participate in and regulate feeding behavior and energy homeostasis. The melanocortin pathway includes five genetic factors that have been demonstrated to mediate weight homeostasis, and when modified, result in obesity. The melanocortin pathway includes the melanocortin agonists, derived from the proopiomelanocortin (POMC) gene, the five G- protein coupled (GPCR) melanocortin receptors identified to date (MC1R-MC5R), and the only two naturally occurring antagonists of GPCRs, agouti (ASP) and agouti-related protein (AGRP) identified to date. The five melanocortin genetic factors that have been identified as being involved in energy homeostasis are the POMC, ASP, AGRP, the brain melanocortin-4 receptor (MC4R), and the melanocortin-3 receptor (MC3R) proteins. These data support the hypothesis that the melanocortin pathway is involved in the regulation of energy homeostasis. The objectives of this research are to develop selective MC3R and MC4R agonists, antagonists, and ligands with mixed receptor pharmacology using peptide and non-peptide combinatorial chemistry libraries and approaches, identify MC3R and MC4R mutations which result in changes in ligand receptor selectivity, identify MC3R mutations which differentiate agonism versus antagonism, and examine MC3R/MC4R selective ligands in vivo using mouse models.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK057080-06A1
Application #
7031939
Study Section
Special Emphasis Panel (ZRG1-EMNR-B (90))
Program Officer
Sechi, Salvatore
Project Start
1999-07-01
Project End
2009-06-30
Budget Start
2005-09-15
Budget End
2006-06-30
Support Year
6
Fiscal Year
2005
Total Cost
$251,194
Indirect Cost
Name
University of Florida
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
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Todorovic, Aleksandar; Ericson, Mark D; Palusak, Ryan D et al. (2016) Comparative Functional Alanine Positional Scanning of the ?-Melanocyte Stimulating Hormone and NDP-Melanocyte Stimulating Hormone Demonstrates Differential Structure-Activity Relationships at the Mouse Melanocortin Receptors. ACS Chem Neurosci 7:984-94
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Singh, Anamika; Haslach, Erica M; Haskell-Luevano, Carrie (2010) Structure-activity relationships (SAR) of melanocortin and agouti-related (AGRP) peptides. Adv Exp Med Biol 681:1-18
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Atalayer, Deniz; Robertson, Kimberly L; Haskell-Luevano, Carrie et al. (2010) Food demand and meal size in mice with single or combined disruption of melanocortin type 3 and 4 receptors. Am J Physiol Regul Integr Comp Physiol 298:R1667-74
Schaub, Jay W; Bruce, Erin B; Haskell-Luevano, Carrie (2010) Drugs, exercise, and the melanocortin-4 receptor-- different means, same ends: treating obesity. Adv Exp Med Biol 681:49-60
Joseph, Christine G; Yao, Hua; Scott, Joseph W et al. (2010) ??-Melanocyte stimulation hormone (??-MSH) truncation studies results in the cautionary note that ??-MSH is not selective for the mouse MC3R over the mouse MC5R. Peptides 31:2304-13

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