# Reversal of Cushing syndrome by antibody-mediated neutralization of ACBP/DBI

## TL;DR

Scientists found that blocking a specific protein can reverse symptoms of Cushing syndrome in mice, even after weight gain and other complications have started.

## Contribution

The study demonstrates that ACBP/DBI inhibition can treat, rather than just prevent, Cushing syndrome in mice.

## Key findings

- Anti-ACBP/DBI monoclonal antibodies normalized food intake and halted weight gain in CORT-treated mice.
- Treatment restored metabolic parameters and reduced fat accumulation and muscle loss caused by CORT.
- Both mouse-specific and cross-species antibodies were effective in reversing Cushing syndrome symptoms.

## Abstract

Cushing syndrome (CS) is caused by an increase in endogenous or exogenous glucocorticoids, leading to major alterations in body composition, including visceral obesity, sarcopenia, osteoporosis, type 2 diabetes, and dyslipidemia. Cardiovascular complications resulting from CS are often lethal. We previously demonstrated that CS induced by oral corticosterone (CORT) supplementation in mice can be prevented by inhibition of the peptide hormone acyl-CoA binding protein (ACBP), encoded by the gene diazepam binding inhibitor (DBI). Here, we investigated whether ACBP/DBI inhibition could be used to treat, rather than prevent, CS. To this end, we initiated treatment with anti-ACBP/DBI monoclonal antibodies (mAbs) in mice three weeks after the start of CORT supplementation, when hyperphagia and body weight gain were already established. Two anti-ACBP/DBI mAbs, 7G4a (specific for mouse ACBP/DBI only) and 82 (which recognizes both mouse and human ACBP/DBI), were able to normalize food intake and halt weight gain in mice under continuous CORT treatment. In addition, both mAbs attenuated CORT-induced sarcopenia, adiposity in inguinal, perigonadal, and visceral fat depots, and fully restored metabolic parameters, including type-2 diabetes, insulinemia, free fatty acids, triglycerides, and liver transaminases. In conclusion, neutralization of ACBP/DBI may serve as an effective therapeutic strategy for the treatment of established CS.