The gliotransmitter ACBP controls feeding and energy homeostasis via the melanocortin system
Khalil Bouyakdan, Hugo Martin, Fabienne Liénard, Lionel Budry, Bouchra Taib, Demetra Rodaros, Chloé Chrétien, Éric Biron, Zoé Husson, Daniela Cota, Luc Pénicaud, Stephanie Fulton, Xavier Fioramonti, Thierry Alquier
Khalil Bouyakdan, Hugo Martin, Fabienne Liénard, Lionel Budry, Bouchra Taib, Demetra Rodaros, Chloé Chrétien, Éric Biron, Zoé Husson, Daniela Cota, Luc Pénicaud, Stephanie Fulton, Xavier Fioramonti, Thierry Alquier
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Research Article Metabolism Neuroscience

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

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–derived (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 suppressed 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.

Authors

Khalil Bouyakdan, Hugo Martin, Fabienne Liénard, Lionel Budry, Bouchra Taib, Demetra Rodaros, Chloé Chrétien, Éric Biron, Zoé Husson, Daniela Cota, Luc Pénicaud, Stephanie Fulton, Xavier Fioramonti, Thierry Alquier

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Figure 2

Genetic rescue of ACBP in GFAP+ astrocytes of the ARC prevents diet-induced obesity.

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Genetic rescue of ACBP in GFAP+ astrocytes of the ARC prevents diet-indu...
(A and B) Immunostaining of GFAP (red) and GFP (green) in GFAP-Cre mice injected with AAV expressing GFP under the control of the GFAP promoter in the ARC (A) and ACBP (red) and GFP (green) in ACBPGFAP KO mice injected with AAV expressing GFP (left, KO-ARCGFP) or ACBP (right, KO-ARCACBP) in the ARC (B). White arrowheads indicate cells coexpressing GFAP and GFP (A) and cells coexpressing ACBP and GFP (B). Scale bars: 100 μm in top panels and 50 μm in zoomed panels (bottom). Representative images from 3 different mice. 3v, third ventricle. (C–E) Acbp expression measured by quantitative PCR in ARC and VMH microdissections (C), and pomc (D) and agrp (E) mRNA levels in ARC microdissections. *P < 0.05, ***P < 0.001, ****P < 0.0001 compared with WT-ARCGFP, 1-way ANOVA with Bonferroni post hoc test, n = 6–9. (F and G) Body weight (F) and cumulative food intake (G) in animals fed with an HFD during 12 weeks. *P < 0.05, **P < 0.01 KO-ARCACBP compared with KO-ARCGFP, 2-way ANOVA with Bonferroni post hoc test, n = 6–9.