Role of ACBP in obesity derived from ciliopathy

Ciliopathies comprise a group of genetic disorders caused by disruptions in primary cilia function, with obesity as a clinical manifestation in some specific cases, such as Alström syndrome (AöS), caused by ALMS1 gene mutations. The link between cilia and lipid metabolism remains elusive, but growing evidence suggests the implication of a non-proficient autophagy. Autophagy affects the intra- and extracellular concentrations of acyl-CoA binding protein (ACBP), which can act as an obesogenic factor. Our study, encompassing multi-omics analyses, revealed early hepatic dyslipidemia, impaired autophagy, and hepatic ACBP accumulation in pre-symptomatic AöS mice. These conditions triggered a lipogenic response and changes in the bacterial microbiota, which were observed in adult AöS mice with obesity. Importantly, the reduction of excessive available ACBP by means of a neutralizing monoclonal antibody prevented weight gain and metabolic defects in Alms1 -/- mice in an autophagy-independent manner. These findings suggest that ciliopathy (in particular AöS)-associated obesity can be treated by ACBP neutralization.