Periodic Reporting for period 3 - AstroNeuroCrosstalk (Astrocyte-Neuronal Crosstalk in Obesity and Diabetes) Reporting period: 2021-01-01 to 2022-06-30 Summary of the context and overall objectives of the project The incidence and prevalence of obesity and its associated comorbidities continue to rise, representing one of the major factors in the leading causes of death confronting modern society. Yet despite considerable efforts aimed at prevention and treatment, no safe and efficient anti-obesity drugs or interventions have had success in tackling this prevalence. Emerging evidence points out that the brain, in particular the hypothalamus, controls most aspects of systemic metabolism, suggesting that obesity may be a disease of the brain. Over the last decades, most studies have been restricted to exploring the functionality of neurons for understanding how the hypothalamus governs feeding behavior and systemic metabolism, ignoring the presence and potential function of other cell types in the brain, such as astrocytes. Increasing evidence highlights that astrocytes are key in the brain’s control of metabolism, positioning them as potential targets for improved pharmacological strategies to prevent and treat metabolic diseases. In summary, I propose to: (Aim 1) understand the ability of astrocytes to release gliotransmitters to neurons, (Aim 2) assess how astrocytes respond to neuronal activity, and (Aim 3) test if high-fat high-sugar diet (HFHS)- induced astrogliosis interrupts this crosstalk and contributes to the development of obesity and type 2 diabetes. Work performed from the beginning of the project to the end of the period covered by the report and main results achieved so far So far, my recent findings indicate that hypothalamic astrocytes are responsible for transducing afferent metabolic cues into neuroendocrine actions for the control of systemic metabolism. In this regard, I observed that hypothalamic astrocytes (i) influence the activity of hunger-sensing neurons to adjust feeding; (ii) regulate the accessibility of metabolic cues from the periphery into the brain for controlling systemic hormone sensitivity; (iii) exhibit diverse responses to hypercaloric diets that might be defined by their functional heterogeneity in the control of metabolism; and (iv) are key for the regulation of pre-autonomic hypothalamic centers to modulate peripheral organ function. Progress beyond the state of the art and expected potential impact (including the socio-economic impact and the wider societal implications of the project so far) Overall, my findings and ongoing projects support that hypothalamic astrocytes are key elements in the neuroendocrine control of metabolism and represent potential cellular targets for therapeutic interventions in obesity. Therefore, my research efforts continue to focus on investigating whether the role of astrocytes and their crosstalk with neurons for the neuroendocrine control of metabolism might be defined by their form, phenotype, and anatomical distribution, as well as their contribution to the progression of obesity and its associated diseases.