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 1

Pan-brain astroglial ACBP deficiency promotes diet-induced obesity.

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Pan-brain astroglial ACBP deficiency promotes diet-induced obesity. (A–D...
(A–D) Body weight and cumulative food intake of male (A and B) and female (C and D) ACBPGFAP WT, HET, and KO mice fed with an HFD during 16 weeks. Insets in B and D represent average weekly food intake. (E–G) Fat mass (E), fat depot weights (F), and fasting plasma leptin levels (G). (H and I) Intraperitoneal glucose tolerance test (IPGTT; 1.5 g/kg) (H) and area under the curve (AUC) (I). (J) Plasma insulin levels during the IPGTT. *P < 0.05, **P < 0.01, ***P < 0.001 compared with control littermates, 2-way ANOVA with Bonferroni post hoc test (A–D and J). *P < 0.05, **P < 0.01, ***P < 0.001 compared with controls, 1-way ANOVA with Bonferroni post hoc test (E and F). **P < 0.01 compared with controls, Student’s t test (G). n = 8–15 for male mice (A, B, and E–J) and 6–7 for female mice (C and D).