Hypothalamic feeding circuits are essential for the maintenance of energy balance. Impairments in this feeding regulatory system cause hyperphagia, which then promotes adiposity and weight gain. However, knowledge of the critical anorexigenic signaling cascade involved in the hypothalamus remains incomplete. ApolipoproteinJ (ApoJ) was not previously suspected to be involved in hypothalamic control of feeding behavior and energy balance. We now have provided the preliminary data that ApoJ functions as such an anorexigenic molecule, targeting leptin signaling and energy balance in the hypothalamus, which could be mediated via the LRP1 (low- density lipoprotein receptor-related protein-1) signaling cascade. We found that centrally administered ApoJ in mice lead to anorexia and weight loss, whereas deletion of hypothalamic ApoJ results in hyperphagia and sever obesity. Specifically, deficiency of ApoJ in astrocytes, but not in AgRP, POMC, and SF-1 neurons, leads to obesity, suggesting that astrocytic ApoJ is important in regulating normal body-weight homeostasis. Like leptin, ApoJ activated Stat3 in leptin receptor (LepR)-expressing neurons but this effect was abolished in LepR- deficient db/db mice, indicating the necessity of LepR signaling for ApoJ's effect. Importantly, ApoJ or leptin- induced food intake was significantly impaired in mice lacking LRP1 in AgRP neurons. Moreover, we found that genetic variant in ApoJ and LRP1 gene is associated with human obesity, suggesting the important link between human disease and ApoJ/LRP1. We thus hypothesize that the ApoJ ? LRP1 axis, coupled with the LepR system, is a novel anorexigenic signaling pathway that is central for the maintenance of normal body- weight homeostasis and energy balance. In this grant, Aim1 will establish the functional importance of ApoJ in astrocytes in the control of energy balance. Aim2 will determine the biological function of LRP1 in regulating energy balance. Aim 3 will elucidate the cellular mechanism(s) underlying the effect of ApoJ on leptin signaling. To accomplish these aims, we will use state-of-the-art technologies, including a conditional floxed ApoJ and LRP1 model to clarify the specific role of ApoJ/LRP1 action and neuron-specific gene manipulation to test cellular mechanisms of ApoJ's anorexigenic action in an in vivo context. These studies provide a unique opportunity to establish a new paradigm in which ApoJ and LRP1 are key determinants of energy balance, and may offer a novel target for the treatment of obesity and diabetes.