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 A number of anorexiants have been withdrawn from clinical development because of their side effects including an increase in depression and suicide.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.

Autophagy in major human diseases

“…While the transient inactivation of autophagy in adipocytes is instrumental to foster the systemic response to nutritional dysregulation, prolonged autophagy inhibition may nonetheless precipitate the obese phenotype, ultimately leading to defective differentiation, proteotoxic stress, and accrued inflammation (Cai et al , 2018 ; Zhang et al , 2018 ). Indeed, a systemic partial autophagy defect, as observed in Atg4b ‐deficient mice, predisposes to diet‐induced obesity (Fernandez et al , 2017 ), and obesity is associated with increased plasma levels of autophagy‐inhibitory factors including DBI/ACBP, both in humans and in mice (Bravo‐San Pedro et al , 2019 ; Joseph et al , 2020 ). Adding to the complexity, the overactivation of autophagy through adipocyte‐specific knockout of Rubcn , a negative regulator of autophagy, markedly impairs the systemic metabolic balance by promoting adipose tissue atrophy and detrimental pile‐up of fat deposits in the liver (Yamamuro et al , 2020 ).…”

Genes Encoding Microbial Acyl Coenzyme A Binding Protein/Diazepam-Binding Inhibitor Orthologs Are Rare in the Human Gut Microbiome and Show No Links to Obesity

“…The appetite-stimulatory effects of ACBP/DBI are lost in mice that bear a phenylalanine (F) to isoleucine (I) substitution at position in the N-terminal domain of the gamma2 subunit of GABAAR (10,47), supporting the contention that this neurotransmitter receptor is responsible for the obesogenic activity of DBI. ACBP/DBI is a GABAAR antagonist, while GABA is a GABAAR agonist.…”

Elevated plasma levels of the appetite-stimulator ACBP/DBI in fasting and obese subjects

“…Of note, in obese humans, an increase in plasma ACBP/DBI levels was observed as well. Thus, in four distinct independent cohorts, ACBP/DBI concentrations significantly correlated with body mass index (BMI), contrasting with reduced circulating ACBP/DBI levels in patients with anorexia nervosa [7,[23][24][25]. Moreover, circulating leukocytes from obese individuals contain more ACBP/DBI mRNA than white blood cells from lean subjects [26], and long-term dietary interventions reduced ACBP/DBI mRNA in subcutaneous fat from obese female patients (600 kcal/d for ten weeks) [27], as well as in visceral fat from non-diabetic men or women with overweight or obesity (800-1000 kcal/d for eight weeks) [28].…”

“…In contrast, intravenous or intraperitoneal administration of recombinant ACBP/DBI protein (isoform 1) to fed mice inhibits autophagy and was sufficient to induce a rapid hyperphagic response [ 7 , 30 ]. This latter effect involves GABA receptors of the A type (GABAAR) because mice bearing a point mutation (F77I) in the GABAAR 2 subunit that reduces ACBP/DBI binding [ 31 ] fail to increase food intake after ACBP/DBI injection [ 24 ]. Thus, the starvation-induced surge in plasma ACBP/DBI may be part of a “hunger reflex” assuring the maintenance of energy and body mass homeostasis [ 32 , 33 ].…”