The prevalence of obesity is increasing in most industrialized nations and is a primary cause of significant health complications, such as heart disease and cancer. At the source of the problem is our inability to control food intake when presented with excess food. It is critical that we understand how reward and motivation circuits of the brain regulate food intake and the nature of the dysfunction that causes obesity. While research has identified the hypothalamus as a critical mediator of peripheral metabolic signals, it is not clear how this is converted into the act of eating. This proposal focuses on a hypothalamic neuropeptide called melanin-concentrating hormone (MCH). MCH is produced in the lateral hypothalamus, a region that has been historically associated with rewarding behavior. Moreover, the MCH receptor is expressed in the nucleus accumbens, a region also studies for reward and drug addiction. Preliminary data is presented to demonstrate that MCH signals to the nucleus accumbens to regulated feeding behavior. Experiments are proposed to elucidate the cellular and molecular effects of MCH receptor signaling in the nucleus accumbens using genomic and phosphoprotein analysis. The results from the proposed experiments will shed light on mechanisms of MCH action in the nucleus accumbens while also serving to provide a better molecular explanation of how neuropeptides regulate complex animal behaviors such as food intak.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM080739-04
Application #
7771745
Study Section
Molecular Neuropharmacology and Signaling Study Section (MNPS)
Program Officer
Dunsmore, Sarah
Project Start
2007-05-01
Project End
2011-02-28
Budget Start
2010-03-01
Budget End
2011-02-28
Support Year
4
Fiscal Year
2010
Total Cost
$288,517
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Biochemistry
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
English, Justin G; Shellhammer, James P; Malahe, Michael et al. (2015) MAPK feedback encodes a switch and timer for tunable stress adaptation in yeast. Sci Signal 8:ra5
Kelley, Joshua B; Dixit, Gauri; Sheetz, Joshua B et al. (2015) RGS proteins and septins cooperate to promote chemotropism by regulating polar cap mobility. Curr Biol 25:275-85
Nagiec, Michal J; McCarter, Patrick C; Kelley, Joshua B et al. (2015) Signal inhibition by a dynamically regulated pool of monophosphorylated MAPK. Mol Biol Cell 26:3359-71
Venkatapurapu, Sai Phanindra; Kelley, Joshua B; Dixit, Gauri et al. (2015) Modulation of receptor dynamics by the regulator of G protein signaling Sst2. Mol Biol Cell 26:4124-34
Dixit, Gauri; Kelley, Joshua B; Houser, John R et al. (2014) Cellular noise suppression by the regulator of G protein signaling Sst2. Mol Cell 55:85-96
Lien, Evan C; Nagiec, Michal J; Dohlman, Henrik G (2013) Proper protein glycosylation promotes mitogen-activated protein kinase signal fidelity. Biochemistry 52:115-24
Jones, Janice C; Jones, Alan M; Temple, Brenda R S et al. (2012) Differences in intradomain and interdomain motion confer distinct activation properties to structurally similar G? proteins. Proc Natl Acad Sci U S A 109:7275-9
Dohlman, Henrik G; Jones, Janice C (2012) Signal activation and inactivation by the G? helical domain: a long-neglected partner in G protein signaling. Sci Signal 5:re2
Jones, Janice C; Duffy, Jeffrey W; Machius, Mischa et al. (2011) The crystal structure of a self-activating G protein alpha subunit reveals its distinct mechanism of signal initiation. Sci Signal 4:ra8
Cappell, Steven D; Dohlman, Henrik G (2011) Selective regulation of MAP kinase signaling by an endomembrane phosphatidylinositol 4-kinase. J Biol Chem 286:14852-60

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