Cristina García Cáceres successfully completed her ERC Project: Astrocyte-Neuronal Crosstalk in Obesity and Diabetes (AstroNeuroCrosstalk)

IDO 1. März 2024

The studies conducted in this ERC project provided 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.

What was the issue being addressed?

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.

What were the overall objectives of the project?

The overarching objectives of this project was 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.

Key Findings

During the funding period, she achieved significant breakthroughs by uncovering the previously underexplored role of hypothalamic astrocytes and novel functional regulators in transducing afferent metabolic cues into neuroendocrine actions critical for the regulation of energy homeostasis. The primary focus of the AstroNeuroCrosstalk project was to elucidate the patho-mechanisms underlying the initiation and progression of obesity, with a specific emphasis on the direct involvement of astrocytes in this phenomenon.

During the funding period, three major results were achieved chronologically:

(1) She discovered that hyperleptinemia drives obesity-induced hypertension through hypothalamic astrocytes, establishing a novel mechanistic link connecting hypothalamic micro-angioarchitecture with systemic blood pressure control (Gruber et al., Cell Metab 2021 - acknowledged with a travel scholarship by Keystone Symposia 2019, Canada - and highlighted by Nat Rev Endocrinol 2021). Over the past decade, the hypothalamus has emerged as a particularly vulnerable brain area in the pathogenesis of diet-induced obesity. This vulnerability may arise from its specialized angioarchitecture with an incomplete blood-brain barrier (fenestrated capillaries). Specifically, she identified a previously unrecognized functional link between astrocyte-mediated dynamic remodeling of the hypothalamic vasculature and the central regulation of systemic blood pressure in response to a high-calorie diet. This study unveiled a novel and significant mechanism that may explain how obesity-associated hyperleptinemia connects microangiopathies with the development of hypertension. Her findings shed light on how obesity-associated hyperleptinemia connects microangiopathies with the development of hypertension, emphasizing the importance of "gliogenic" mechanisms in tuning sympathetic outflow.

(2) She revealed that a distinct diet-responsive astrocyte population within the hypothalamus, suggesting its potential role in metabolic control defined by form, phenotype, anatomical distribution, and contribution to obesity progression (Lutomska et al., Glia 2023). Given the crucial role of hypothalamic astrocytes in metabolic control, rapidly responding to a hypercaloric diet before notable changes in body weight and peripheral inflammation signs (Garcia-Caceres et al., 2019; Gonzalez-Garcia and Garcia-Caceres, 2021), she further explored if astrocytes exhibit distinct responses based on their anatomical location. Her findings indicate that long-term exposure to a hypercaloric diet affects the transcriptional pattern of astrocytes in the cortex, hippocampus, and hypothalamus, with the most significant changes observed in the proteomic profile of hypothalamic astrocytes. Unlike other hypothalamic cell types, astrocytes quickly respond to the hypercaloric diet, undergoing temporal and spatial reorganization, revealing distinct molecular states. This study provides a foundation for understanding the cellular circuitries in the hypothalamus and their diet-induced rearrangements, showcasing their high susceptibility to respond to a hypercaloric diet even before substantial changes occur.

(3) She identified that Estradiol regulates leptin sensitivity to control feeding via hypothalamic Cited1 (Gonzalez-Garcia et al., Cell Metab 2023 - highlighted by Nat Rev Endocrinol 2023 and Trends Endocrinol Metab 2023). The growing awareness of sexual dimorphism in how the brain, particularly the hypothalamus, regulates energy homeostasis and metabolic adaptation to diet-induced obesity emphasizes the necessity of considering sex as a biological variable. Her findings reveal that Cited1 acts as a novel neuroendocrine factor, crucial for integrating peripheral endocrine cues from gonadal and adipose axes into melanocortin neurons, contributing to metabolic adaptation in diet-induced obesity. Her results further demonstrate that Cited1 participates in the convergence and translation of estrogens and leptin signaling into a hypothalamic neuronal response required for fine-tuning food intake and body weight homeostasis in obesity.

Why is this research important for society?

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.

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