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Astrocyte-Neuronal Crosstalk in Obesity and Diabetes

Periodic Reporting for period 4 - AstroNeuroCrosstalk (Astrocyte-Neuronal Crosstalk in Obesity and Diabetes)

Reporting period: 2022-07-01 to 2023-12-31

This research addresses a critical gap in prior studies, primarily focusing on investigating the neuronal role in understanding the regulation of feeding behavior and systemic metabolism by the hypothalamus. It has previously overlooked the potential contributions and functions of non-neuronal cells, specifically astrocytes, in regulating feeding circuits and controlling systemic metabolism. The studies conducted in this project aim to provide a more comprehensive understanding of how the hypothalamus controls energy balance and metabolic adaptations in response to hypercaloric diets, thereby contributing to our understanding of its dysfunction and its link to obesity.
The significance of this study for society lies in understanding the cellular players through which the hypothalamus controls energy homeostasis. By revealing the role of astrocytes and the mechanisms they mediate in the regulation of hypothalamic feeding circuits, this research aims to elucidate how these non-neuronal cells function as crucial elements. This knowledge is essential for a comprehensive understanding of systemic metabolic control and the mechanisms underlying the initiation and progression of metabolic diseases such as obesity, a prominent health concern in contemporary society.
The overarching objectives of this proposal were to unravel the intricate functional interactions between neurons and their adjacent astroglia within the hypothalamus. By exploring the location of the interface between neurons and blood vessels, the research aims to delineate how alterations in these glial cells contribute to the development of obesity. Ultimately, the study seeks to provide valuable insights that can guide strategies to prevent and treat obesity and associated comorbidities, such as hypertension.
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.
In summary, her research outcomes and ongoing projects highlight the crucial role of hypothalamic astrocytes in the neuroendocrine regulation of metabolism. These findings position astrocytes as promising targets for therapeutic interventions in obesity. Notably, she has uncovered novel regulators within the hypothalamus that play a significant role in integrating peripheral endocrine cues from the gonadal and adipose axes into melanocortin neurons, contributing to metabolic adaptation in diet-induced obesity. The overarching objective is to unravel how various factors, including sex as a variable, influence the progression of obesity and its associated diseases.
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