The role of the Ghrelin Receptor in appetite and energy metabolism

Ghrelin is a stomach hormone secreted into the bloodstream that acts on ghrelin receptors (GHSR1a) in the hypothalamus to increase food intake and regulate energy metabolism. This review focuses on the role of the GHSR1a in the hypothalamus and highlights the function the different nuclei expressing the GHSR1a. We discuss the mechanisms through which ghrelin activates receptors on NPY neurons and downstream signaling within NPY neurons. The downstream signaling involves a number of key metabolic signaling nodes including CaMKK, AMPK, CPT1, UCP2 and SIRT1 pathways that enhances mitochondrial efficiency and buffers reactive oxygen species in order to maintain an appropriate firing response in NPY. Finally, we examine a new model of synaptic plasticity in hypothalamic feeding circuits in which ghrelin activates GHSR1a on presynaptic glutamatergic inputs onto NPY and switches on an AMPK-dependent feed-for- ward system. This model of synaptic plasticity ensures sustained NPY firing during periods of negative energy balance. Taken together, we detail a number of novel mechanisms through which ghrelin signaling via the GHSR1a maintains high NPY neuronal activity in order to promote food intake under conditions of negative energy balance.