Metabolic and Autophagic Control by Acyl CoA Binding Protein (ACBP/DBI) – ACBP-DBI

we propose the in-depth characterization of the DBI system. We will explore the mechanism governing DBI expression in various tissues, the mechanisms explaining its ATG-dependent release from cells, its pharmacology (pharmacokinetics of DBI and its fragments, effects of DBI on its receptors and signalling pathways), elaborate strategies to elevate its expression (by transgenes or by supply of recombinant DBI protein) or neutralization (by inducible knockout, induction of DBI-autoantibodies, or external supply of in-house monoclonal antibodies), and characterize the effects of DBI on metabolism using a battery of distinct methods, while attempting to establish a hierarchy among autophagy-regulatory and diverse metabolic effects. Special attention will be devoted to the question how the peripheral (intraperitoneal or intravenous) administration of DBI or anti-DBI antibodies can affect central appetite control.

In mice, the plasma concentrations of the appetite-stimulatory and autophagy-inhibitory factor ACBP/DBI acutely increase in response to starvation, but also do so upon chronic overnutrition leading to obesity. We found that knockout of Acbp/Dbi in adipose tissue is sufficient to prevent high-fat diet-induced weight gain in mice. We investigated ACBP/DBI plasma concentrations in several patient cohorts to discover a similar dual pattern of regulation. In relatively healthy subjects, ACBP/DBI concentrations independently correlated with body mass index (BMI) and age. The association between ACBP/DBI and BMI was lost in subjects that underwent major weight gain in the subsequent 3-9 years, as well as in advanced cancer patients. Voluntary fasting, undernutrition in the context of advanced cancer, as well as chemotherapy were associated with an increase in circulating ACBP/DBI levels.

Altogether, these results support the conclusion that ACBP/DBI may play an important role in body mass homeostasis as well as in its failure.

8 papers

This research project is inspired by yet unpublished observations implying the protein diazepam binding protein (DBI)/acyl CoA-binding protein (ACBP) in the control of autophagy, peripheral metabolism, and appetite. This notion is based on the observations that DBI serum levels correlate with human corpulence (low in anorexia, high in obesity) and that injecting DBI into mice causes hyperphagy (and activation of orexigenic neurons) and weight gain with increased fat deposition, while its neutralization reduces feeding (and activates anorexigenic neurons) and entails weight loss with lipolysis. Incidentally, the secretion of DBI from cells in vitro and in vivo is unconventional and depends on autophagy genes (ATGs). DBI also controls autophagy, meaning that injection of DBI into mice inhibits autophagy, while its neutralization induces autophagic flux. Moreover, DBI has major effects on metabolism affecting glycaemia, fatty acid oxidation, as well as anabolic and catabolic metabolism in adipose tissues and the liver. Based on these results, we propose the in-depth characterization of the DBI system. We will explore the mechanism governing DBI expression in various tissues, the mechanisms explaining its ATG-dependent release from cells, its pharmacology (pharmacokinetics of DBI and its fragments, effects of DBI on its receptors and signalling pathways), elaborate strategies to elevate its expression (by transgenes or by supply of recombinant DBI protein) or neutralization (by inducible knockout, induction of DBI-autoantibodies, or external supply of in-house monoclonal antibodies), and characterize the effects of DBI on metabolism using a battery of distinct methods, while attempting to establish a hierarchy among autophagy-regulatory and diverse metabolic effects. Special attention will be devoted to the question how the peripheral (intraperitoneal or intravenous) administration of DBI or anti-DBI antibodies can affect central appetite control.