Adaptive and maladaptive astrocyte-neuron communication in the aetiology of metabolic syndrome – AstrObesity

The brain controls energy balance by adapting feeding and energy expenditure to nutrient availability. Disruption of this regulation results in obesity and metabolic pathologies. In the brain, the hypothalamus is regarded as a fundamental player in body weight regulation. First order neurons in the arcuate nucleus of the hypothalamus are located near one of the circumventricular organs allowing selective exchange of blood-borne substances. Amongst secondary target hypothalamic nuclei, the paraventricular nucleus (PVN) is a crucial autonomic nervous system/neuroendocrine center involved in the regulation and coordination of homeostatic functions. Molecularly distinct PVN populations of neurons are instrumental in the control of feeding, energy expenditure and neuro-hormonal response. Although the role of astrocytes, the major type of glial cells in the brain, has been well studied in neurodegenerative disorders, their implication in the central control of energy balance has only recently come to forefront. Hypothalamic neurons are known to control energy balance, however their activity and the adequate delivery of energy substrates are tightly dependent on astrocytes. Astrocytes form extensive networks and occupy a strategic position in brain circuits, at the interface between blood vessels and neurons. Obesity as well as high energy food intake were shown to trigger inflammatory-like response in hypothalamic astrocytes in association with dysregulation of neurometabolic coupling. Hence, obesity and nutrient-induced alteration of astrocytic network plasticity, metabolism, nutrient transport and transmitter release might be the bedrock of a primary central defect that will ultimately lead to impaired central control of energy homeostasis. However, until recently the direct causal role of hypothalamic astrocytes in the development and maintenance of metabolic diseases has been largely overlooked.
The consortium gathered here has the ambition to expand the understanding of the central cause of the metabolic syndrome beyond the neuro-centrist approach by demonstrating that functional remodeling of hypothalamic astrocytes in response to nutrient overload represents a key step in the development of obesity and associated disorders.
Research hypothesis. The present proposal “AstrObesity” builds on existing results and preliminary data acquired in collaboration between partners 1, 2 & 3 together with data published by Partner 2. The PVN represents a pivotal hypothalamic autonomic/neuroendocrine control center. Our data collected in vivo show that chemogenetic and pharmacological manipulation of PVN astrocytes exert a differential control on metabolic parameters in lean and obese animals. The next step is to understand cellular and sub-cellular mechanisms linking astrocytes to metabolic responses. The driving hypothesis of AstrObesity is that nutrient overload and obesity promote maladaptive changes regarding the structural and functional properties of astrocytes and astrocyte-neuron communication, thereby leading to impaired central control of food intake, energy expenditure and glucose metabolism.

Objectives. Driven by preliminary data suggesting that nutrient overload promotes dysfunctional changes in astrocytes function and astrocyte-neuron communication within the PVN, the overarching goal of AstrObesity is to understand whether and how maladaptive astrocyte-neuron communication is a key process in the etiology of the metabolic syndrome and to provide a mechanistic framework for the identification and the conception of testable molecular targets for glia-oriented therapies against obesity and associated disorders.