Acyl-CoA binding protein for the experimental treatment of anorexia

• DOI: 10.1126/scitranslmed.adl0715
• Publication Date: 2024-08-14T17:58:31Z
• Authors: Hui Chen; Stéphanie Moriceau; Adrien Joseph; Francois Mailliet; Sijing Li; Virginie Tolle; Philibert Duriez; Roland Dardennes; Sylvère Durand; Vincent Carbonnier; Gautier Stoll; Allan Sauvat; Sylvie Lachkar; Fanny Aprahamian; Carolina Alves Co...; Hui Pan; Léa Montégut; Gerasimos Anagnos...; Flavia Lambertucci; Omar Motiño; Uxía Nogueira-Rec...; Mélanie Bourgin; Misha Mao; Yuhong Pan; Alexandra Cerone; Erwan Boedec; Zelia L. Gouveia; Federica Marmorino; Chiara Cremolini; Lisa Derosa; Laurence Zitvogel; Oliver Kepp; Carlos López-Otín; Maria Chiara Maiuri; Franck Perez; Philip Gorwood; Nicolas Ramoz; Franck Oury; Isabelle Martins; Guido Kroemer
• Keywords: Diazepam Binding Inhibitor; Male; Restraint, Physical; autophagy; endozepine; obesity; 0303 health sciences; Anorexia Nervosa; Hypothalamus; body mass index; Mice, Transgenic; [SDV.BC]Life Sciences [q-bio]/Cellular Biology; Anorexia; Mice, Inbred C57BL; Mice; 03 medical and health sciences; appetite control; Lipocalin-2; Hepatocytes; Animals; Humans; Female; metabolism

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.