Obesity is increasingly prevalent and leads to a variety of life-threatening diseases including diabetes, stroke, heart disease and cancers, and has huge economic consequences. Studies on obesity clearly indicate important roles for hypothalamic peptide transmitters in regulating aspects of energy homeostasis. Recently, we have shown that in addition to peptide transmitters, hypothalamic neurons expressing the proopiomelanocortin (POMC) gene, which potently affect energy balance, also release the fast-acting amino acid transmitters GABA and glutamate. The primary goal of this proposal is to test the hypothesis that amino acid transmitters released from POMC neurons play a key role in the regulation of energy balance, and that perturbing GABA and glutamate release from these neurons will affect food intake and body weight. This hypothesis will be tested by 1) determining how GABA and glutamate release from POMC neurons is regulated by fasting and food intake using in situ hybridization and optogenetic stimulation/electrophysiologic techniques. And 2) by determining the result of transiently or persistently disrupting GABA and glutamate release from POMC neurons specifically by using selective knockout approaches, as well as by manipulating POMC neuron activity using designer receptors exclusively activated by designer drugs (DREADD) technology. The consequence of disrupted GABA or glutamate release on energy balance regulation will be determined. Altogether, the results will indicate if POMC neurons affect energy balance circuits via two distinct mechanisms: peptides and amino acid transmitters. It may be that amino acid transmitters in feeding circuits will prove to be viable targets for manipulating energy balance regulation.

Public Health Relevance

Obesity contributes to about 112,000 deaths per year and is the primary reason for over $75 billion in health care expenditures in the United States. A better understanding of how the brain regulates energy balance is a key step towards developing therapeutic approaches to prevent and treat obesity. This study will determine how specific transmitters from neurons known to alter energy balance are contributing to body weight regulation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK078749-06A1
Application #
8629274
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Hyde, James F
Project Start
2007-07-01
Project End
2018-07-31
Budget Start
2013-09-12
Budget End
2014-07-31
Support Year
6
Fiscal Year
2013
Total Cost
$316,312
Indirect Cost
$98,812
Name
Colorado State University-Fort Collins
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
785979618
City
Fort Collins
State
CO
Country
United States
Zip Code
80523
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