1. Acyl-CoA binding protein for the experimental treatment of anorexia.
- Author
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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, and Motiño, Omar
- Subjects
CARRIER proteins ,MELANOCORTIN receptors ,EATING disorders ,PEPTIDES ,ANOREXIA nervosa ,PACLITAXEL - Abstract
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. Editor's summary: Despite its seriousness, anorexia nervosa has limited treatment options. Chen et al. report that acyl CoA binding protein (ACBP), a conserved peptide known to induce hunger, is particularly low in hospitalized anorexic patients with poor prognosis. Administration of ACBP by chemogenetic, daily intravenous, or subcutaneous osmotic pump approaches in mouse models of stress- or chemotherapy-induced anorexia promoted food intake, suggesting the peptide as a potential treatment option for anorexia nervosa. Although ACBP treatment led to dampened hypothalamic MC4R signaling in the mice, the protein did not cross the blood-brain barrier. Its complete mechanism of action thus remains to be elucidated. —Catherine Charneski [ABSTRACT FROM AUTHOR]
- Published
- 2024
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