The PI, Cristina Garcia-Caceres, launched the project based on evidence that astrocytes translate metabolic cues into neuroendocrine actions. These cells react to hormones and nutrients, influencing neuronal activity in hypothalamic circuits, particularly in glucose metabolism and feeding behavior. Positioned near blood vessels, astrocytes control the access of circulating cues into the brain. During the funding period, three major discoveries were achieved: 1) Hypothalamic astrocytes control blood pressure in obesity (Gruber et al., Cell Metab 2021). The hypothalamus is vulnerable in diet-induced obesity due to its specialized angioarchitecture with an incomplete blood-brain barrier. A functional link was found between astrocyte-mediated remodeling of the hypothalamic vasculature and systemic blood pressure regulation in response to a high-calorie diet. This study explained how obesity-associated hyperleptinemia connects microangiopathies with hypertension, emphasizing "gliogenic" mechanisms in tuning sympathetic outflow. 2) A hypercaloric diet triggers transient molecular rearrangements in hypothalamic astrocytes (Lutomska et al., Glia 2022). Astrocytes rapidly respond to a hypercaloric diet before notable changes in body weight and peripheral inflammation. Long-term exposure affects astrocytes' transcriptional pattern across the brain, with significant changes in hypothalamic astrocytes. This study revealed distinct molecular states in astrocytes due to hypercaloric diet, showcasing their high susceptibility to dietary changes. 3) Estradiol regulates leptin sensitivity via hypothalamic Cited1 to control feeding (González-García et al., Cell Metab 2023). The research highlighted sexual dimorphism in brain regulation of energy homeostasis and metabolic adaptation to diet-induced obesity. Cited1 acts as a neuroendocrine factor, integrating cues from gonadal and adipose axes into melanocortin neurons, aiding metabolic adaptation in obesity. Cited1 translates estrogens and leptin signaling into a neuronal response for food intake and body weight regulation. This study, highlighted in Nat Rev Endocrinol (2023) and Trends Endocrinol Metab (2023), contributed to understanding sex differences in obesity pathogenesis. The research outcomes were published in high-impact journals and presented at international conferences, including EMBO, Keystone, and Helmholtz Diabetes Conference. Cristina expanded her teaching with lectures at top universities and received awards for neuroscience and obesity research. With over 50 invited talks, her work increased international visibility and fostered scientific networks. As the Associate Director of the Institute for Diabetes and Obesity and Head of the Astrocyte-Neuron Network Unit at Helmholtz Munich, Cristina continues to explore astrocytes' role in metabolic control and their interaction with peripheral cues in obesity, promising targets to combat these diseases.
