SHAPE · Role of estrogen signaling to astrocytes in the hypothalamus in the development of obesity.

Obesity is a complex condition that causes around 1.6 million deaths each year. The metabolic alterations to an obesigenic environment are highly dependent on the sex of the individual. In the brain, the hypothalamus controls energy homeostasis by fine tuning feeding and energy expenditure to nutrient availability. Disruption of this regulation results in obesity. While hypothalamic neurons are crucial for the control of energy balance, their activity is tightly dependent on adequate delivery of energy substrates provided by astrocytes, the major type of glial cells in the brain. Whether nutritional challenges evoke sex-specific astrocyte adaptations and its contribution to the sex-dimorphism in the pathogenesis of obesity remains unknown. Interestingly, estrogen signaling is an essential target that mediates sexual differentiation in the brain. This project’s main aim is to determine the role of estrogen signaling in astrocytes in: 1) hypothalamic astrocytic adaptations to obesity, 2) energy metabolism in lean and obese conditions and 3) in the beneficial effects of incretin-based therapies against obesity. The present proposal intends to combine interdisciplinary expertise in astrocyte biology and neural control of metabolism to expand the understanding on the involvement of hypothalamic astrocytes in the development of obesity in a sex-dependent manner. The cutting-edge approach of ex vivo and in vivo astrocyte-selective targeting of estrogen signaling in specific hypothalamic areas, extends beyond the neuro-centrist approach by demonstrating that functional remodeling of hypothalamic astrocytes in response to nutrient overload represents a key step for the development of novel cell-selective therapeutic approaches for treating obesity and associated pathologies.