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Acyl-CoA binding protein for the experimental treatment of anorexia

Affiliations
  • 1Centre de Recherche des Cordeliers, Equipe labellisée par la Ligue contre le cancer, Inserm U1138, Université Paris Cité, Sorbonne Université, 75006 Paris, France.
  • 2Metabolomics and Cell Biology Platforms, Gustave Roussy Institut, 94805 Villejuif, France.
  • 3Faculté de Médecine, Université de Paris Saclay, Kremlin Bicêtre, 91400 Paris, France.
  • 4Institut Imagine, Platform for Neurobehavioral and Metabolism, Structure Fédérative de Recherche Necker, 26 INSERM US24/CNRS UAR, 3633, 75015 Paris, France.
  • 5Service de Réanimation Médicale, Hôpital Saint-Louis, Assistance Publique Hôpitaux de Paris, 75010 Paris, France.
  • 6Université Paris Cité, INSERM UMR-S1151, CNRS UMR-S8253, Institut Necker Enfants Malades, Team 8, F-75015 Paris, France.
  • 7Université de Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Genetic Vulnerability to Addictive and Psychiatric Disorders Team, 75015 Paris, France.
  • 8Université Paris Cité and GHU Paris Psychiatrie et Neurosciences, CMME, Hôpital Sainte-Anne, 75014 Paris, France.
  • 9Gustave Roussy Cancer Campus, 94805 Villejuif Cedex, France.
  • 10Université Paris-Saclay, Faculté de Médecine, 94800 Le Kremlin-Bicêtre, France.
  • 11Institut National de la Santé Et de la Recherche Médicale (INSERM) U1015, Équipe Labellisée-Ligue Nationale contre le Cancer, 94805 Villejuif, France.
  • 12Rheumatology Research Group (GIR), Biomedical Research Institute of A Coruña (INIBIC), Professor Novoa Santos Foundation, 15006 A Coruña, Spain.
  • 13Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, 310016 Hangzhou, Zhejiang, China.
  • 14Université Paris Cité, Institute of Psychiatry and Neuroscience of Paris (IPNP), INSERM U1266, Biochemistry and Biophysics (B&B) Core Facility, 75014 Paris, France.
  • 15Cell Biology and Cancer Unit, Institut Curie, PSL Research University, CNRS, 75005 Paris, France.
  • 16Unit of Medical Oncology 2, Azienda Ospedaliero Universitaria Pisana, 56126 Pisa, Italy.
  • 17Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56126 Pisa, Italy.
  • 18Facultad de Ciencias de la Vida y la Naturaleza, Universidad Nebrija, 28248 Madrid, Spain.
  • 19Departamento de Bioquímica y Biología Molecular, Instituto Universitario de Oncología (IUOPA), Universidad de Oviedo, 33006 Oviedo, Spain.
  • 20Department of Molecular Medicine and Medical Biotechnologies, University of Naples Federico II, 80131 Naples, Italy.
  • 21Institut du Cancer Paris CARPEM, Department of Biology, Hôpital Européen Georges Pompidou, AP-HP, 75015 Paris, France.

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August 14, 2024

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.

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