Identification of ACBP as a potential target in ciliopathic obesity through multi-omics network analysis

Ciliopathies are genetic disorders characterized by defective primary cilia function, with obesity as a clinical manifestation in certain cases, including Alström syndrome, which is caused by ALMS1 mutations. The link between cilia and lipid metabolism remains poorly understood, but evidence suggests a role for impaired autophagy. Autophagy affects both intra- and extracellular levels of ACBP, which can act as an obesogenic factor. Our multi-omics study reveals early hepatic dyslipidemia, impaired autophagy, and hepatic accumulation of ACBP in presymptomatic male mice lacking Alms1 gene. These conditions are consistent with the obesogenic phenotype and with alterations in the gut microbiota that manifest as the mice age and develop obesity. Importantly, reducing excessive ACBP with a neutralizing monoclonal antibody limits weight gain and metabolic defects in Alms1^-/- mice in an autophagy-independent manner. Altogether, the data support the idea that ciliopathy-associated obesity, particularly Alström syndrome, may be mitigated by ACBP neutralization.