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
View: Text | PDF
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

×

Figure 4

Central effects of ODN on energy homeostasis rely on the melanocortin system.

Options: View larger image (or click on image) Download as PowerPoint
Central effects of ODN on energy homeostasis rely on the melanocortin sy...
(A–I) Cumulative food intake of C57BL/6J WT (n = 10–15) (A), MC4R-KO (n = 10–11) (D), and ob/ob (n = 5–6) (G) overnight-fasted (16 hours) male mice following i.c.v. administration of 100 ng of ODN or saline control. RER and locomotor activity in C57BL/6J WT (B and C), MC4R-KO (E and F), and ob/ob (H and I) mice measured in CLAMS metabolic cages during 24 hours following i.c.v. ODN or saline after 24 hours of acclimation. *P < 0.05, **P < 0.01, ***P < 0.001 compared with saline controls, 2-way ANOVA with Bonferroni post hoc test. (J and K) Acbp expression measured by quantitative PCR in ARC (n = 11–14) and VMH (n = 4–5) microdissections (J) and pomc in ARC microdissections (n = 8) (K) from C57BL/6J WT male mice injected bilaterally in the ARC with AAV expressing GFP (WT-ARCGFP) or ACBP (WT-ARCACBP) under the control of the GFAP promoter. ***P < 0.001 compared with WT-ARCGFP, Student’s t test. (L and M) Body weight gain (L) and cumulative food intake (M) in WT-ARCGFP and WT-ARCACBP mice (n = 12–15). *P < 0.05, **P < 0.01 compared with WT-ARCGFP, 2-way ANOVA with Bonferroni post hoc test.