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

Abstract

Eukaryotic cells release the phylogenetically ancient protein acyl coenzyme A binding protein (ACBP, which in humans is encoded by the gene DBI, diazepam binding inhibitor) upon nutrient deprivation. Accordingly, mice that are starved for one to two days and humans that undergo voluntary fasting for one to three weeks manifest an increase in the plasma concentration of ACBP/DBI. Paradoxically, ACBP/DBI levels also increase in obese mice and humans. Since ACBP/DBI stimulates appetite, this latter finding may explain why obesity constitutes a self-perpetuating state. Here, we present a theoretical framework to embed these findings in the mechanisms of weight control, as well as a bioinformatics analysis showing that, irrespective of the human cell or tissue type, one single isoform of ACBP/DBI (ACBP1) is preponderant (~90% of all DBI transcripts, with the sole exception of the testis, where it is ~70%). Based on our knowledge, we conclude that ACBP1 is subjected to a biphasic transcriptional and post-transcriptional regulation, explaining why obesity and fasting both are associated with increased circulating ACBP1 protein levels.

An obesogenic feedforward loop involving PPARγ, acyl-CoA binding protein and GABAA receptor

“…Thus, it appears that long-term variations in BMI are coupled with a loss of the homeostatic “hunger reflex” giving rise to a permanent and pathogenic alteration of the setpoint of the system. In a hypothetical obesogenic feedforward loop, overeating would cause an increase in ACBP levels, which in turn favors excessive food intake [ 23 ].…”

Immunization of mice with the self-peptide ACBP coupled to keyhole limpet hemocyanin

“…ACBP is a phylogenetically conserved protein ( Charmpilas et al., 2020 ; Madeo et al., 2020 ) that is ubiquitously expressed intracellularly in mammals and released into the circulation upon starvation ( Bravo-San Pedro et al., 2019b ; Bravo-San Pedro et al., 2019c ). ACBP exists in several isoforms, among which ACBP1 is the most abundant one in both human and murine tissues as well as in the circulation ( Li et al., 2021 ). Extracellular ACBP stimulates appetite, reduces fatty acid oxidation, and stimulates lipid accumulation in adipose tissues.…”

Acyl coenzyme A binding protein (ACBP): An aging‐ and disease‐relevant “autophagy checkpoint”

“…In contrast to ACBP/DBI which is expressed ubiquitously by most if not all cell types, ACBD7 / Acbd7 and Dbi5 expression appears to be restricted to a few organs such as brain, testis, and ovary (Lanfray et al, 2016 ) (Figure 1b ). Although multiple ACBP/DBI splice variants have been reported, only one single isoform (ACBP1) accounts for >90% of all ACBP / DBI transcripts in all human organs with the sole exception of the testis where it represents ~70% (Li et al, 2021 ). At this point, there is little or no information on the gonad‐ or brain‐specific functions of these mammalian ACBP/DBI homologues and isoforms apart from the anorexigenic effects of an ACBD7‐derived nonadecaneuropeptide (NDN) acting on the hypothalamus (Lanfray et al, 2016 ).…”