Splice-switching oligonucleotides (SSOs) modulating Scarb1 splicing revert the accumulation of lipotoxic species in RBFOX2-deficient mouse hepatocytes, alleviate liver inflammation associated with diet-induced obesity in vivo and promote an anti-atherogenic lipoprotein profile in the blood, demonstrating the potential of isoform-specific RNA therapeutics for metabolic pathologies. Here, SCARB1 is linked to obesity due to melanocortin 4 receptor deficiency.