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J Clin Invest. 2019 Apr 2;130:2417-2430. doi: 10.1172/JCI123454.

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

Author information

1
Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montreal Diabetes Research Center, and Departments of Medicine, Pathology and Cell Biology, Biochemistry, Neurosciences, and Nutrition, Université de Montréal, Montreal, Quebec, Canada.
2
Université de Bordeaux, INRA, NutriNeuro, Bordeaux, France.
3
Bordeaux INP, NutriNeuro, Talence, France.
4
Centre des Sciences du Goût et de l'Alimentation, UMR 6265 CNRS, 1324 INRA, Université de Bourgogne Franche-Comté, Dijon, France.
5
Faculty of Pharmacy, Université Laval and Laboratory of Medicinal Chemistry, Centre de Recherche du Centre Hospitalier Universitaire de Québec (CRCHUQ), Quebec, Quebec, Canada.
6
INSERM, Université de Bordeaux, Neurocentre Magendie, Physiopathologie de la Plasticité Neuronale, U1215, Bordeaux, France.
7
Stromalab, CNRS ERL 5311, Université de Toulouse, Université Paul Sabatier, Toulouse, France.

Abstract

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.

KEYWORDS:

Melanocortin; Metabolism; Neuroendocrine regulation; Neuroscience; Obesity

PMID:
30938715
PMCID:
PMC6546475
[Available on 2019-09-03]
DOI:
10.1172/JCI123454
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