The gliotransmitter ACBP controls feeding and energy homeostasis via the melanocortin system

• Published in: The Journal of clinical investigation 2019-06, Vol.129 (6), p.2417-2430
• Main Authors: Bouyakdan, Khalil, Martin, Hugo, Liénard, Fabienne, Budry, Lionel, Taib, Bouchra, Rodaros, Demetra, Chrétien, Chloé, Biron, Éric, Husson, Zoé, Cota, Daniela, Pénicaud, Luc, Fulton, Stephanie, Fioramonti, Xavier, Alquier, Thierry
• Format: Article
• Language: English
• Subjects: ACBP protein; Animal models; Animals; Anorexia nervosa; Apposition; Arcuate nucleus; Astrocytes; Astrocytes - metabolism; Astrocytes - pathology; Biomedical research; Body weight gain; Body weight loss; Cell Line; Clonal deletion; Development and progression; Diabetes; Diazepam Binding Inhibitor - genetics; Diazepam Binding Inhibitor - metabolism; Diazepam-binding inhibitor; Eating; Endocrinology and metabolism; Energy; Energy balance; Energy Metabolism; Etiology; Etiology (Medicine); Fatty acids; Feeding; Female; G protein-coupled receptors; Gene expression; Glial cells; Glial fibrillary acidic protein; Glucose; Glucose tolerance; Homeostasis; Human health and pathology; Hyperphagia; Hyperphagia - genetics; Hyperphagia - metabolism; Hyperphagia - pathology; Hypothalamus; Life Sciences; Male; Melanocortin; Melanocyte stimulating hormone; Metabolism; Metabolites; Mice; Mice, Knockout; Neurobiology; Neurons; Neurons - metabolism; Neurons - pathology; Neurons and Cognition; Neuropeptides; Obesity; Obesity - genetics; Obesity - metabolism; Obesity - pathology; Octadecaneuropeptide; Peptides; Pro-Opiomelanocortin - genetics; Pro-Opiomelanocortin - metabolism; Proopiomelanocortin; Protein binding; Proteins; Rodents; Tanycytes; Tissues and Organs; Weight control; γ-Aminobutyric acid A receptors
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI123454

Glial cells have emerged as key players in the central control of energy balance and etiology of obesity. Astrocytes play a central role in neural communication via the release of gliotransmitters. Acyl-CoA binding protein (ACBP)-derived endozepines are secreted peptides that modulate the GABAA receptor. In the hypothalamus, ACBP is enriched in arcuate nucleus (ARC) astrocytes, ependymocytes and tanycytes. Central administration of the endozepine octadecaneuropeptide (ODN) reduces feeding and improves glucose tolerance, yet the contribution of endogenous ACBP in energy homeostasis is unknown. We demonstrated that ACBP deletion in GFAP+ astrocytes, but not in Nkx2.1-lineage neural cells, promoted diet-induced hyperphagia and obesity in both male and female mice, an effect prevented by viral rescue of ACBP in ARC astrocytes. ACBP-astrocytes were observed in apposition with proopiomelanocortin (POMC) neurons and ODN selectively activated POMC neurons through the ODN-GPCR but not GABAA, and supressed feeding while increasing carbohydrate utilization via the melanocortin system. Similarly, ACBP overexpression in ARC astrocytes reduced feeding and weight gain. Finally, the ODN-GPCR agonist decreased feeding and promoted weight loss in ob/ob mice. These findings uncover ACBP as an ARC gliopeptide playing a key role in energy balance control and exerting strong anorectic effects via the central melanocortin system.