Acyl-CoA-binding protein (ACBP): a phylogenetically conserved appetite stimulator

Abstract

Recently, we reported that, in mice, hunger causes the autophagy-dependent release of a protein called "acyl-CoAbinding protein" or "diazepam binding inhibitor" (ACBP/DBI) from cells, resulting in an increase in plasma ACBP concentrations. Administration of extra ACBP is orexigenic and obesogenic, while its neutralization is anorexigenic in mice, suggesting that ACBP is a major stimulator of appetite and lipo-anabolism. Accordingly, obese persons have higher circulating ACBP levels than lean individuals, and anorexia nervosa is associated with subnormal ACBP plasma concentrations. Here, we investigated whether ACBP might play a phylogenetically conserved role in appetite stimulation. We found that extracellular ACBP favors sporulation in Saccharomyces cerevisiae, knowing that sporulation is a strategy for yeast to seek new food sources. Moreover, in the nematode Caenorhabditis elegans, ACBP increased the ingestion of bacteria as well as the frequency pharyngeal pumping. These observations indicate that ACBP has a phylogenetically ancient role as a 'hunger factor' that favors food intake. Recently, we identified acyl-CoA-binding protein (ACBP), also known as diazepam binding inhibitor (DBI), as a novel appetite stimulating factor 19. Indeed, plasma concentrations of ACBP are elevated in obese patients, as well as in mice that were rendered obese by a high-fat diet

Reactive oxygen species triggers unconventional secretion of antioxidants and Acb1

“…Although Acb1 is not known as an antioxidant, it is emerging as an important lipogenic signaling factor secreted upon starvation in metazoans (Bravo-San Pedro et al, 2019; Ryuda et al, 2011). We suggest ROS produced during starvation acts as a signal to release a variety of proteins that include antioxidants in order to maintain cells in a metabolically active, but otherwise dormant form (e.g., sporulation in yeast and Dictyostelium discoideum ; Charmpilas et al, 2020; Duran et al, 2010; Kinseth et al, 2007; Manjithaya et al, 2010), until their return to normal growth conditions.…”

“…The release of Acb1 and SOD1 is triggered by nutrient starvation upon culturing yeast in potassium acetate. The secreted Acb1 in lower eukaryotes, such as yeast and slime mold, functions in signaling and regulating the starvation-induced cell differentiation program of sporulation (Anjard et al, 1998; Charmpilas et al, 2020; Kinseth et al, 2007; Manjithaya et al, 2010). In the human brain, the Acb1 orthologue ACBP (also known as Diazepam binding inhibitor) modulates GABA (γ-Aminobutyric Acid) receptor signaling, and, more recently in whole animals, ACBP has been identified as an important lipogenic signaling factor (Costa and Guidotti, 1991; Gandolfo et al, 2001; Bravo-San Pedro et al, 2019).…”

Antibody-mediated neutralization of ACBP/DBI has anorexigenic and lipolytic effects

“…Of note genetic evidence obtained in yeasts, nematodes and mice supports the notion that ACBP/DBI stimulates food-seeking behaviour across the phylogenic treat, meaning that the ablation of the genes coding for ACBP/DBI inhibits sporulation (in Saccharomyces cerevisiae), pharyngeal pumping (in Caenorhabditis elegans) and food intake (in mice) [11]. Moreover, human obesity was found to be coupled to an increase in ACBP/DBI mRNA expression in white adipose tissue, as well as to an elevation in plasma ACBP/DBI levels [8].…”

ACBP is an appetite stimulator across phylogenetic barriers

“…Ste3 is a seventransmembrane G-protein-coupled receptor that responds to the mating-type a-factor pheromone to facilitate cytogamy (cell-to-cell fusion) between haploid gametes during the mating process. In addition, yeast ACBP/DBI stimulates Ste3-dependent sporulation, which may constitute an advantage in conditions of starvation because it allows yeast to move to other food sources [7].…”

“…In sum, it appears that ACBP/DBI has an appetitestimulatory role across phylogeny, from yeast to nematodes, flies, mice and (presumably) humans (Figure 1). That said, there are species specificities, because ACBP/DBI acts on a metabotropic receptor (Ste3) in yeast, but on ionotropic gamma-aminobytyric (GABA) A receptors in mice [7], suggesting that the effector of ACBP/DBI have changed during evolution. Moreover, in yeast it appears that the genetic removal of ACBP/DBI inhibits autophagy, contrasting with findings in C. elegans, mice and human cell cultures in which removal ACBP/DBI stimulates autophagy [5,7].…”