Obesity afflicts millions of people, and is a major risk factor for Type II diabetes and morbidity. The melanocortin pathway has been clearly identified in mice and humans to be involved in the regulation of obesity and energy homeostasis. Five melanocortin genetic factors that have been identified as being involved in energy homeostasis (the proopiomelanocortin agonists, Agouti and Agouti-related protein antagonists, and the melanocortin-4 receptor and the melanocortin-3 receptor proteins). In 2007, endogenous beta-defensin peptides were reported to participate in the melanocortin pathway. To date, a very limited number of "safe and effective" drugs that result in decreased obesity are currently marketed or in the pipeline. There are many reasons for this, however a critical obstacle is that not all the molecules, factors, proteins, receptors, and pathways that are involved in obesity have been identified and mechanistically characterized. One such example is the beta-defensins. Our working hypothesis is that the endogenous beta-defensin ligands regulate melanocortin receptor function. It is unclear the specific molecular interactions and mechanisms by which the beta-defensins interact with the melanocortin receptors. Are they agonists or antagonists? What are the receptor subtype selectivity profiles? What are the putative ligand-receptor interactions? The proposed multidisciplinary approaches to answer the above questions include chemistry and in vitro receptor pharmacology. This proposal seeks to clarify this novel endogenous melanocortin receptor ligand family, gain fundamental knowledge, and develop molecular probes to use to determine their potential involvement with obesity and Type 2 diabetes.

Public Health Relevance

Obesity afflicts millions of people, and is a major risk factor for Type 2 diabetes and morbidity. The melanocortin pathway has been clearly identified humans to be involved in the regulation of obesity, energy homeostasis, and Type 2 diabetes. To date, a very limited number of safe and effective drugs that result in decreased obesity are currently marketed or in the pipeline. There are many reasons for this, however a critical obstacle is that not all the molecules produced by the body involved in the control of obesity have been identified and scientifically characterized. The proposed studies seek to characterize a newly discovered class of molecules, the beta-defensins, and how they regulate the melanocortin pathway at the molecular level. These goals are important for target validation and rational design of molecules as potential therapeutic agents regarding obesity, type 2 diabetes, and associated diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
1R01DK097838-01
Application #
8416242
Study Section
Special Emphasis Panel (ZRG1-DDNS-C (01))
Program Officer
Pawlyk, Aaron
Project Start
2012-12-01
Project End
2016-11-30
Budget Start
2012-12-01
Budget End
2013-11-30
Support Year
1
Fiscal Year
2013
Total Cost
$416,490
Indirect Cost
$137,132
Name
University of Minnesota Twin Cities
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455