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.
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.
| Üner, Aykut; Gonçalves, Gabriel H M; Li, Wenjing et al. (2015) The role of GluN2A and GluN2B NMDA receptor subunits in AgRP and POMC neurons on body weight and glucose homeostasis. Mol Metab 4:678-91 |
| 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 |
| Ha, Sangdeuk; Baver, Scott; Huo, Lihong et al. (2013) Somato-dendritic localization and signaling by leptin receptors in hypothalamic POMC and AgRP neurons. PLoS One 8:e77622 |
| Coppari, Roberto; Bjørbæk, Christian (2012) Leptin revisited: its mechanism of action and potential for treating diabetes. Nat Rev Drug Discov 11:692-708 |
| Huang, Hu; Kong, Dong; Byun, Kyung Hee et al. (2012) Rho-kinase regulates energy balance by targeting hypothalamic leptin receptor signaling. Nat Neurosci 15:1391-8 |
