Periodic Reporting for period 1 - AstroCOMET (Astrocyte-neuron COmmunication in METabolism and obesity.)
Période du rapport: 2020-04-01 au 2022-03-31
Obesity and its associated comorbidities, such as type 2 diabetes, have become highly prevalent in our society and represent two major health threats for the future. Recent epidemiological data from the WHO showed that more than 1.9 billion adults aged 18 years and older are overweight and over 650 million adults are obese. Overall, about 13% of the world’s adult population (11% of men and 15% of women) is obese. The situation has reached epidemic proportions globally, with at least 2.8 million people dying each year as a result of being overweight or obese. This medical problem is the consequence of an energy imbalance between calories consumed and calories expended, but the fundamental pathophysiological causes leading to this imbalance are still not properly understood. In addition, despite decades of research, the development of safe and effective anti-obesity treatments has not been successful enough to correct the increasing presence of both maladies. The current state of the art, have identified the brain as the main regulator of systemic metabolism, suggesting that obesity has a brain-centered context. In particular, the hypothalamus acts as a center of the metabolic homeostasis by integrating constant inputs from circulating nutrients and endocrine signals and generating the appropriate physiological responses to maintain a balanced systemic metabolism and a stable body weight. While decades of investigations have resulted in major insights into how hypothalamic neurons govern feeding behavior and systemic metabolism, recent work suggests that the current model is constrained by the assumption that neurons are the only brain cell types involved in the central control of energy homeostasis. In particular, astrocytes, have recently been shown to be involved in the functional regulation of metabolism. For instance, high fat diet (HFD) induces metabolic and morphological disturbances in the hypothalamus including changes in its cytoarchitecture affecting how astrocytes interact physically with pro-opiomelanocortin (POMC) and neuropeptide Y (NPY) neurons in the hypothalamus – essential neuronal populations for the maintenance of energy homeostasis. Moreover, it has recently been reported that insulin receptors (IRs) in astrocytes were important players for the regulation of glucose homeostasis. Overall, together these results suggest a new paradigm in which astrocytes interplay with neurons for the CNS control of metabolism, body weight, and energy balance. However, the mechanisms by which astrocytes communicate with neurons to adjust the activity of feeding circuits and systemic metabolism in response to whole body energy demands remains to be investigated. Therefore, the overall objective of the AstroCOMET project was to study the role of hypothalamic astrocytes in the control of metabolism and how alterations in their function could be part of the obesity pathophysiology.
In order to examine whether astrocyte activity is required for maintaining a normal energy homeostasis we used Designer Receptors Exclusively Activated by Designer Drugs (DREADD) technology to activate astrocytes located in the arcuate nucleus of the hypothalamus (ARC). The chronic activation of astrocytes induced an increase in body weight. We also measured body composition of these mice through EchoMRI and found a higher adiposity with no changes in lean mass. To precisely monitor the metabolic status of the mice, we subjected them to indirect calorimetry using TSE metabolic cages. We found that astrocytes in the ARC modulate hyperphagia in a light-dark phase dependent manner. Activation of astrocytes in the ARC was also associated with an increase in energy expenditure, locomotor activity, and a higher respiratory exchange ratio. In order to understand if the communication established between astrocytes and neurons in the ARC was the key component of the phenotypic changes observed, we combined two different DREADD strategies to activate astrocytes and inhibit neuronal activity at the same time. Results obtained showed that concomitant AgRP neuronal inhibition together with astrocyte chemogenetic activation blunted the observed increase in food intake, energy expenditure, locomotor activity, and respiratory exchange ratio. In order to test whether astrocytes release vesicles to regulate the activity of hypothalamic neurons in the control of energy metabolism we tested two specific transgenic mouse models, dnSNARE and iBOT lines; however, we found technical difficulties to validate both models. Proper monitoring of the project risks helped us find an early solution to this drawback following an alternative strategy to address the same aim. We used a virogenetic model to express tetanus neurotoxin (TeNT) in ARC astrocytes and thus test whether astrocytes communicate with neurons for the control of metabolism via the release of vesicles. We performed experiments injecting astrocyte expressing-TeNT and found that gliotransmission through vesicles did not induce changes in energy balance under chow diet conditions. In order to investigate whether astrocyte-neuron communication might contribute to obesity progression we evaluated the metabolic phenotype of high fat diet fed mice by interfering with astrocytic release of gliotransmitter-containing vesicles. TeNT-astrocyte specific expression induced a decrease in food intake compared to control animals after high fat diet exposure. Finally, in order to understand how astrocytes integrate endocrine signals in the context of obesity we generated a post-natal double knock out of the insulin receptor and the insulin growth factor 1 receptor in astrocytes. Metabolic phenotyping of this mouse line showed that animals develop a resistance to weight gain under HFD, indicating that insulin signaling in astrocytes plays a role in the development of diet induced-obesity. Results generated were disseminated in the scientific community via internal seminars and international congresses. In addition, we have published several papers related to the astrocyte-neuron communication in metabolism and additional manuscripts are currently in preparation for submission into scientific journals. Moreover, results were also communicated to a general audience as an outreach activity through the “Science is Wonderful” initiative.
Findings obtained in the AstroCOMET project have provided new insights into the hypothalamic mechanisms that control feeding behavior and body weight. Our results support a model where astrocyte-neuron communication in the hypothalamus is a key element in the neuroendocrine control of metabolism and represents a novel mechanism in the development of obesity. Interestingly, findings obtained here suggest that astrocyte-neuron communication is playing a role in the early phase of obesity development and thus may be a target for future therapeutic interventions in obesity. The technological approaches designed here, the knowledge obtained, and the fruitful scientific environment generated will reinforce our research center in particular, and strengthen the future socio-economic impact in the neuroendocrine scientific community in general. The basic science developed here has also set the grounds for future discoveries about astrocytes neurobiology in the field of obesity.