PROJECT SUMMARY The staggering prevalence of obesity in the United States poses major public health concerns. Since energy balance regulation is coordinated by CNS centers, investigation into the underlying homeostatic, brain mechanisms controlling feeding behavior and weight management is critical to the development of novel and efficacious obesity therapeutics. The proposed research focuses on the role of astrocytes in the nucleus tractus solitarius (NTS) of the caudal brainstem in mediating the food intake and body weight suppressive effects of adipocyte derived hormone leptin. While the vast majority of studies have investigated neuronal processing of leptin signaling, little is known about the contribution of non-neuronal cells such as astrocytes. Collectively, the critical role of astrocytes in modulating neuronal excitability, synaptic efficiency, and plasticity of metabolic circuits in addition to recent evidence demonstrating expression of the leptin receptor (LepRb) on astrocytes, suggests NTS astrocytes are a prime cellular target for central leptin signaling. The main goal of this proposal is to train the fellowship applicant in a variety of in vivo techniques to investigate the role of caudal brainstem LepRb-expressing astrocytes in the integration of energy status signals and the long-term reductions in food intake and body weight produced by LepRb activation in both male and female rats. Preliminary evidence shows that pharmacological blockade of NTS astrocytes significantly attenuates the acute hypophagic effect of centrally administered leptin. Therefore, Specific Aim I tests the hypothesis that NTS astrocytes are pharmacologically and physiologically relevant in mediating the energy balancing effects of leptin. Leptin's influence on energy balance also occurs, in part, by potentiating neuronal processing of gastrointestinal (GI)-derived satiation signals at the level of the caudal brainstem. Specific Aim II involves a series of behavioral and neuroanatomical experiments to examine this potential contribution of NTS astrocytes in modulating GI-derived satiation signals and the synergistic interaction between NTS leptin signaling and these GI satiation signals. An important component of these proposed aims is to (1) investigate the effects of high fat diet on astrocytic leptin signaling and (2) identify any potential sexual dimorphisms in the contribution of NTS astrocytes to control energy balance. Overall, results from these experiments will determine the functional relevance of LepRb signaling on NTS astrocytes in metabolic homeostasis and/or as novel target for the treatment of obesity and importantly prepare the fellow for an independent research career.