TY - JOUR
T1 - The gliotransmitter ACBP controls feeding and energy homeostasis via the melanocortin system
AU - Bouyakdan, Khalil
AU - Martin, Hugo
AU - Liénard, Fabienne
AU - Budry, Lionel
AU - Taib, Bouchra
AU - Rodaros, Demetra
AU - Chrétien, Chloé
AU - Biron, Éric
AU - Husson, Zoé
AU - Cota, Daniela
AU - Pénicaud, Luc
AU - Fulton, Stephanie
AU - Fioramonti, Xavier
AU - Alquier, Thierry
N1 - Funding Information:
We are grateful to S. Mandrup for the ACBP-floxed mice. We are thankful to A. Lefranc, L. Decocq, and A. Mathou for animal care. We thank the CRCHUM rodent metabolic phenotyping core facility for their help with CLAMS and MRI studies and the cell biology and physiology core facility for hormone assays. We thank S. Luquet (Université Paris Diderot) for insightful discussions. We are grateful to S. Audet (CRCHUM) for his help with qPCR. This work was supported by grants from the Canadian Institutes of Health Research (MOP115042 and PJT153035 to TA); the Marie Curie Foundation (CIG NeuROSenS PCIG09-GA-2011-293738 to XF); Société Francophone du Diabète and Diabète Québec (to TA); Réseau de recherche en santé cardiométabolique, diabète et obésité from Fonds de Recherche Québec-Santé (CMDO-FRQS; to TA and XF); and INSERM, Agence Nationale Recherche (ANR-13-BSV4-0006 and ANR-18-CE14-0029-02 to DC, and ANR-10-LABX-43 Labex BRAIN to DC and XF). HM and CC were supported by a fellowship from the department AlimH INRA and the Région Nouvelle Aquitaine (HM) or Région Bourgogne (CC). XF and LP were also supported by the PARI Région Bourgogne. TA, SF, and EB were supported by a salary award from FRQS. KB and BT were supported by a fellowship from Diabète Québec and LB by a fellowship from Diabetes Canada.
Publisher Copyright:
© 2019, American Society for Clinical Investigation.
PY - 2019/6/3
Y1 - 2019/6/3
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI123454
DO - 10.1172/JCI123454
M3 - Article
C2 - 30938715
AN - SCOPUS:85064202934
SN - 0021-9738
VL - 129
SP - 2417
EP - 2430
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 6
ER -