The gliotransmitter ACBP controls feeding and energy homeostasis via the melanocortin system
Khalil Bouyakdan, … , Xavier Fioramonti, Thierry Alquier
Khalil Bouyakdan, … , Xavier Fioramonti, Thierry Alquier
Published June 3, 2019; First published April 2, 2019
Citation Information: J Clin Invest. 2019;129(6):2417-2430. https://doi.org/10.1172/JCI123454.
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Categories: 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 5

ODN activates POMC neurons through a GABAA-independent but ODN GPCR–dependent mechanism.

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ODN activates POMC neurons through a GABAA-independent but ODN GPCR–depe...
(A) Representative voltage-clamp whole-cell recording of a POMC neuron with or without 1 nM ODN. (B and C) Quantification of sIPSC frequency (B) and amplitude (C) of POMC and non-POMC neurons before and during ODN application. *P < 0.05 compared with control, paired Student’s t test, n = 5–6 neurons from 5–6 mice. (D) Representative cell-attached recording of a POMC neuron in the presence of bicuculline, picrotoxin, cyanquixaline, and APV before and during ODN application (1 nM). (E) Quantification of AP frequency in POMC neurons with or without the inhibitors and ODN (1 nM). *P < 0.05 compared with inhibitors (PTX/BCC), 1-way ANOVA repeated measures with Bonferroni post hoc test, n = 10 neurons from 10 mice. (F) Quantification of AP frequency of POMC neurons before and during cOP (2 nM) application. *P < 0.05 compared with control, paired Student’s t test, n = 6 neurons from 4 mice. (G) Cumulative food intake in overnight-fasted (16 hours) C57BL/6 WT male mice following i.c.v. administration of 50 ng of cOP or saline (n = 9–10). (H and I) Cumulative food intake (H) and percent body weight change (I) following daily i.c.v. administration of 50 ng of cOP or saline in ad libitum–fed ob/ob mice (n = 6–8). (G–I) *P < 0.05, **P < 0.01, ***P < 0.001 compared with saline, 2-way ANOVA with Bonferroni post hoc test.