Neutralization of DBI/ACBP for the prevention of ciliopathy-associated obesity

Obesity is a feature of only a subset of ciliopathies, including Alström syndrome, a rare genetic disorder caused by ALMS1 deficiency. In our recent work, we applied integrative multi-omics network analysis to one of these ciliopathies that develop with obesity, the <i>Alms1</i>-deficient mouse model and identified DBI/ACBP (diazepam binding inhibitor, acyl-CoA binding protein) as a central driver of ciliopathy-associated obesity. We found that ALMS1 deficiency induces early hepatic dyslipidemia accompanied by impaired macroautophagy/autophagy and pathological accumulation of DBI/ACBP, preceding overt obesity. Importantly, prophylactic DBI/ACBP neutralization with monoclonal antibodies prevents weight gain and metabolic alterations without restoring autophagic markers, indicating that DBI/ACBP acts as an obesogenic effector downstream of, or parallel to, defective autophagy. These findings position DBI/ACBP as a metabolically relevant autophagy-associated regulator in ciliopathy and suggest that therapeutic benefit can be achieved by targeting autophagy-linked effectors without directly correcting autophagic flux. This punctum discusses our results in the context of hepatic autophagy and lipid metabolism, highlighting DBI/ACBP as a mechanistic link between ciliary dysfunction, altered autophagy, and metabolic disease.