An RNA thermogenic therapy to preserve lean mass and enhance metabolic health during GLP-1 weight loss
Abstract
Significance Current antiobesity therapies reduce body weight but often induce loss of lean mass and fail to achieve durable metabolic improvements after treatment ends. We show that an adipose-targeted RNA therapeutic targeting ZFP423, a transcriptional repressor of brown and beige fat identity, enhances thermogenesis and energy expenditure to complement glucagon-like peptide-1 receptor agonist (GLP-1RA) treatment. Suppression of ZFP423 promotes white adipose beiging and improves systemic metabolism in mice, and when combined with GLP-1RA produces greater fat loss than either treatment alone while preserving lean mass. These results identify Zfp423 as an RNA therapeutic target and leverage adipose thermogenesis as a clinical adjuvant to GLP-1RA for obesity pharmacotherapy.