Metabolic and psychiatric effects of acyl coenzyme A binding protein (ACBP)/diazepam binding inhibitor (DBI).

Abstract

Acyl coenzyme A binding protein (ACBP), also known as diazepam binding inhibitor (DBI) is a multifunctional protein with an intracellular action (as ACBP), as well as with an extracellular role (as DBI). The plasma levels of soluble ACBP/DBI are elevated in human obesity and reduced in anorexia nervosa. Accumulating evidence indicates that genetic or antibody-mediated neutralization of ACBP/DBI has anorexigenic effects, thus inhibiting food intake and inducing lipo-catabolic reactions in mice. A number of anorexiants have been withdrawn from clinical development because of their side effects including an increase in depression and suicide. For this reason, we investigated the psychiatric impact of ACBP/DBI in mouse models and patient cohorts. Intravenously (i.v.) injected ACBP/DBI protein conserved its orexigenic function when the protein was mutated to abolish acyl coenzyme A binding, but lost its appetite-stimulatory effect in mice bearing a mutation in the γ2 subunit of the γ-aminobutyric acid (GABA) A receptor (GABAAR). ACBP/DBI neutralization by intraperitoneal (i.p.) injection of a specific mAb blunted excessive food intake in starved and leptin-deficient mice, but not in ghrelin-treated animals. Neither i.v. nor i.p. injected anti-ACBP/DBI antibody affected the behavior of mice in the dark-light box and open-field test. In contrast, ACBP/DBI increased immobility in the forced swim test, while anti-ACBP/DBI antibody counteracted this sign of depression. In patients diagnosed with therapy-resistant bipolar disorder or schizophrenia, ACBP/DBI similarly correlated with body mass index (BMI), not with the psychiatric diagnosis. Patients with high levels of ACBP/DBI were at risk of dyslipidemia and this effect was independent from BMI, as indicated by multivariate analysis. In summary, it appears that ACBP/DBI neutralization has no negative impact on mood and that human depression is not associated with alterations in ACBP/DBI concentrations.

• Authors: Adrien Joseph, Stéphanie Moriceau, Valentina Sica, Gerasimos Anagnostopoulos, Jonathan Pol, Isabelle Martins, Antoine Lafarge, Maria Chiara Maiuri, Marion Leboyer, Josephine Loftus, Frank Bellivier, Raoul Belzeaux, Fabrice Berna, Bruno Etain, Delphine Capdevielle, Philippe Courtet, Caroline Dubertret, Julien Dubreucq, D' Amato Thierry, Guillaume Fond, Sebastien Gard, Pierre-Michel Llorca, Jasmina Mallet, David Misdrahi, Emilie Olié, Christine Passerieux, Mircea Polosan, Paul Roux, Ludovic Samalin, Franck Schürhoff, Raymond Schwan, FACE-SZ and FACE-BD (FondaMental Academic Centers of Expertise, for Schizophrenia and for Bipolar Disorder) Groups, Christophe Magnan, Franck Oury, José M Bravo-San Pedro, Guido Kroemer
• Journal: Cell death & disease (Cell Death Dis) Vol. 11 Issue 7 Pg. 502 (07 06 2020) ISSN: 2041-4889 [Electronic] England
• PMID: 32632162 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Diazepam Binding Inhibitor
• Receptors, GABA-A

Topics

• Animals
• Appetite
• Behavior, Animal
• Body Mass Index
• Darkness
• Diazepam Binding Inhibitor (blood, metabolism)
• Feeding Behavior
• Immobilization
• Male
• Mental Disorders (blood, diagnosis, metabolism)
• Metabolic Syndrome (blood)
• Mice, Inbred C57BL
• Receptors, GABA-A (metabolism)
• Swimming (physiology)