Métabolisme astrocytaire des acides gras et gliotransmission dans l’hypothalamus : deux fonctions de l’Acyl-CoA Binding Protein impliquées dans le contrôle de l’homéostasie énergétique

Obesity is the most prevalent metabolic disorder in North America and is a major risk factor for the development of various pathologies including type 2 diabetes. Obesity is caused by nutritional intake overtaking energy expenditure. Thus, the body needs to be able to accurately assess its nutritional status and modulate the energy balance accordingly to maintain a healthy body weight. This role can be ascribed to the mediobasal hypothalamus (MBH), a brain region known for its implication in the maintenance of glucose homeostasis and energy balance. Specifically, the arcuate nucleus is able to detect both metabolic and hormonal signals from the periphery, such as glucose, fatty acids, insulin and leptin. These signals act on the activity of two distinct neuronal populations, orexigenic NPY neurons and anorectic POMC neurons, to control food intake, energy expenditure and glucose homeostasis. The mechanisms and cell type involved in hypothalamic fatty acid sensing and subsequent effects on food intake and energy homeostasis remain to be elucidated. It is thus crucial to understand the mechanisms by which our body assesses its nutritional status and acts to maintain a stable energy balance. The first aim of my thesis was to characterize central fatty acid metabolism. We aim to identify which cell type in the brain is involved in their metabolism. We also aim to evaluate if and how fatty acid metabolism is modulated by glucose. Our data suggest that, in the brain, astrocyte have the highest capacity to use and oxidize fatty acids. We also show a coupling between glucose and fatty acid metabolism that relies on the AMP-activated kinase (AMPK) and is specific to the hypothalamus. Indeed, fatty acid oxidation was regulated by glucose in astrocytes and brain slices from the hypothalamus, but not from the cortex. Finally, we show that palmitate, but not oleate, oxidation and esterification are coupled to glucose. Our findings reveal a metabolic coupling of glucose and fatty acid metabolism in the brain specific to hypothalamic areas as well as to fatty acid type. The second aim of my thesis was to characterize astrocyte fatty acid metabolism. We thus focused on Acyl-CoA Binding Protein (ACBP), a protein involved in fatty acid metabolism in peripheral tissue that, in the brain, is almost exclusively found in astrocytes. We looked to determine whether astrocyte fatty acid metabolism is regulated by ACBP and if saturated and unsaturated fatty acids metabolism is differentially regulated. We show that ACBP can regulate unsaturated, but not saturated, fatty acid oxidation and esterification in both astrocytes and hypothalamic slices. Finally, the third aim of my thesis was the in vivo regulation of food intake by ACBP as well as the identification of a potential mechanism by which ACBP and its cleaved peptide octadecaneuropeptide (ODN) modulate energy balance. Our data show that an astrocyte specific ACBP loss of function increases susceptibility to high fat diet induced obesity. Our data also suggest that the anorectic action of ODN (cleaved from ACBP) involves a direct activation of POMC neurons in the arcuate nucleus via a G protein coupled receptor. Taken together, our findings support the essential role of astrocytes in hypothalamic fatty acid metabolism and their ability to detect various circulating nutrients such as glucose and fatty acids. Our data sheds light on a potentially new mechanism of modulation of food intake and energy expenditure via a direct activation of POMC neurons by ACBP. Thus, the anorectic action of unsaturated fatty acid could require their binding and/or intracellular metabolism by ACBP. These new data could lead to the identification of a clinically relevant target for the treatment of various feeding disorders that could lead to pathologies like obesity and type 2 diabetes.

Keyphrases: ACBP, Astrocytes, Gliotransmission, Hypothalamus, ODN, POMC, Endozepines, Energy expenditure, Fatty acids, Food intake, Obesity