PROJECT SUMMARY The immune system is an important and dynamic regulator of metabolism. In peripheral tissues, over-nutrition and obesity lead to marked changes in immune cell population, causing associated shifts in signaling and tissue function. While type I immunity is associated with the release of pro-inflammatory cytokines and insulin resistance, type II immunity has been shown to promote beige fat biogenesis, glucose homeostasis, and energy balance. In the brain, activation of the pro-inflammatory NF-kB signaling pathway can lead to hyperphagia and metabolic dysfunction. Whether activation of type II immune signaling pathways can restore energy balance and protect against obesity has not yet been investigated. IL-13 is a Th2 cytokine that signals through its cellular receptor IL-13R1. Whole body deletion of Il13ra1 causes obesity and loss of blood glucose homeostasis. Il13ra1 is expressed in the subtantia nigra and ventral tegmental area of the brain. Preliminary data show that specific deletion of Il13ra1 from the dopaminergic midbrain at least partially reproduces the metabolic phenotypes of the whole-body knockout. The substantia nigra and ventral tegmental area are the primary producers of dopamine in the CNS. Numerous studies have related central dopamine activity to energy balance. In this study, we will test the hypothesis that central IL-13 signals through its receptor in the dopaminergic midbrain to maintain energy balance. We will investigate the cellular and molecular mechanisms by which it does so. We will use both gain-of-function and loss-of-function genetic models to test our hypothesis. Knowledge from this study is expected to fill major gaps in our understanding of how the immune system interacts with the nervous system to coordinate metabolic regulation, and also to identify novel pathways in the CNS that modulate energy balance.