The fat-derived hormone leptin acts on neurons in the hypothalamus to regulate food intake and body weight in rodents and humans.
The aim of this proposal is to identify and characterize a novel signaling mechanism whereby leptin affects neuronal activity of POMC and AgRP neurons. Specifically, we will test the hypothesis that leptin receptors localized on dendrites of POMC and AGRP neurons regulates phosphorylation and activity of post-synaptic glutamate receptors (NMDA-R(NR1/NR2B)), and that this pathway influences dendrite morphology, and eventually plays a role in energy balance regulation in mice. To achieve this, we will investigate leptin receptor signaling and action in cell lines, primary neuronal cultures, brain slices and in vivo in mice. We will use state- of-the art methodologies and create/use novel genetically modified mice, and study leptin's effects on neuronal plasticity and on energy balance in mice lacking specific NMDA receptor subunits in POMC or AgRP neurons. Findings from this proposal will lead to a significant advancement in our understanding of leptin receptor neurobiology. We will elucidate a new CNS pathway whereby leptin regulates energy balance.

Public Health Relevance

We aim to identify a novel mechanism whereby leptin inhibits caloric intake in mice. Obtained data are important for advancing our understanding of how the brain controls appetite and body weight. The results are relevant for the future development of new strategies aimed at helping humans suffering from obesity.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK094040-03
Application #
8661767
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Hyde, James F
Project Start
2012-05-19
Project End
2016-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
$372,795
Indirect Cost
$144,855
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Gonçalves, Gabriel H M; Li, Wenjing; Garcia, Adriana V C-G et al. (2014) Hypothalamic agouti-related peptide neurons and the central melanocortin system are crucial mediators of leptin's antidiabetic actions. Cell Rep 7:1093-103