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Acyl-CoA binding protein for the experimental treatment of anorexia

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Chen, Hui | Moriceau, Stéphanie | Joseph, Adrien | Mailliet, Francois | Li, Sijing | Tolle, Virginie | Duriez, Philibert | Dardennes, Roland | Durand, Sylvère | Carbonnier, Vincent | Stoll, Gautier | Sauvat, Allan | Lachkar, Sylvie | Aprahamian, Fanny | Alves Costa Silva, Carolina | Pan, Hui | Montégut, Léa | Anagnostopoulos, Gerasimos | Lambertucci, Flavia | Motiño, Omar | Nogueira-Recalde, Uxía | Bourgin, Mélanie | Mao, Misha | Pan, Yuhong | Cerone, Alexandra | Boedec, Erwan | Gouveia, Zelia | Marmorino, Federica | Cremolini, Chiara | Derosa, Lisa | Zitvogel, Laurence | Kepp, Oliver | López-Otín, Carlos | Maiuri, Maria Chiara | Perez, Franck | Gorwood, Philip | Ramoz, Nicolas | Oury, Franck | Martins, Isabelle | Kroemer, Guido

Edité par CCSD ; American Association for the Advancement of Science (AAAS) -

International audience. Extracellular acyl-coenzyme A binding protein [ACBP encoded by diazepam binding inhibitor (DBI)] is a phylogenetically ancient appetite stimulator that is secreted in a nonconventional, autophagy-dependent fashion. Here, we show that low ACBP/DBI plasma concentrations are associated with poor prognosis in patients with anorexia nervosa, a frequent and often intractable eating disorder. In mice, anorexia induced by chronic restraint stress (CRS) is accompanied by a reduction in circulating ACBP/DBI concentrations. We engineered a chemical-genetic system for the secretion of ACBP/DBI through a biotin-activatable, autophagy-independent pathway. In transgenic mice expressing this system in hepatocytes, biotin-induced elevations in plasma ACBP/DBI concentrations prevented anorexia induced by CRS or chemotherapeutic agents including cisplatin, doxorubicin, and paclitaxel. ACBP/DBI reversed the CRS or cisplatin-induced increase in plasma lipocalin-2 concentrations and the hypothalamic activation of anorexigenic melanocortin 4 receptors, for which lipocalin-2 is an agonist. Daily intravenous injections of recombinant ACBP/DBI protein or subcutaneous implantation of osmotic pumps releasing recombinant ACBP/DBI mimicked the orexigenic effects of the chemical-genetic system. In conclusion, the supplementation of extracellular and peripheral ACBP/DBI might constitute a viable strategy for treating anorexia.

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