Role of Neuronal PKA Signaling in Energy Homeostasis

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Project Summary Obesity has reached epidemic levels in the United States in recent years. Understanding the neural mechanisms underlying feeding behavior has thus become a critical undertaking. Although we are beginning to get a better understanding of the neural circuits that control energy homeostasis, the intracellular signaling mechanisms remain relatively unknown. Long term control over feeding behavior involves a hypothalamic circuit. Pro- opiomelanocortin (POMC), and agouti related peptide (AgRP) neurons in the arcuate nucleus respond to peripheral hormones including leptin and ghrelin and then signal to the melanocortin receptor 4 (MC4R) neurons in the paraventricular hypothalamic nucleus (PVH) to control energy homeostasis. This proposal seeks to determine the role of Protein Kinase A (PKA) within this pathway. I will virally express a Cre dependent dominant negative RIα subunit of PKA, AAV-flex-RIαB-mCherry, or Cre dependent Gαs coupled designer receptor activated by designer drugs (DREADD), AAV-flex-GsD-mCherry, in AgRP-Cre expressing mice. These state-of- the-art techniques will allow us to determine the effect of suppressing or stimulating PKA on feeding behavior. By combining our previously developed technique of immunoprecipitating polyribosomes (RiboTag) we will also be able to examine the role of PKA signaling in nutritionally regulated mRNA translation in AgRP neurons. Further studies will utilize the RIB and GsD expressing virus to determine what role PKA plays in the response of MC4R-Cre expressing neurons to the MC4R ligand, MSH. The PKA signaling pathway is well suited to pharmacological manipulation by agonists and antagonists of G-protein coupled receptors, phosphodiesterase inhibitors, and kinase activators and inhibitors. Our proposal seeks to identify potential targets within hypothalamic neurons that might be exploited to modulate feeding behavior as a therapeutic approach to the treatment of obesity.