Systemic Inhibition of Frizzled4 Rewires Adipose and Hepatic Metabolism in Obesity
Frizzled-4 (FZD4), a Wnt receptor best known for its role in developmental processes such as retinal vascularization, is here identified as a critical regulator of metabolic homeostasis. We show that Fzd4 is highly enriched in mature adipocytes and further upregulated by high-fat diet feeding. Systemic Fzd4 knockdown reduced body weight, adipose mass, and serum triglyceride levels while improving glucose tolerance. Transcriptomic profiling of inguinal white adipose tissue (iWAT) revealed suppression of Wnt/beta-catenin-dependent lipogenesis, activation of lipolytic programs, and induction of immune signaling pathways. Unexpectedly, enhanced lipolysis redistributed lipids to the liver, driving hepatic triglyceride accumulation and reprogramming of lipid-handling and glycogen metabolism. In contrast, depot-restricted Fzd4 knockdown reduced local lipogenesis without altering systemic energy balance, highlighting tissue-specific effects of FZD4 signaling. These findings uncover FZD4 as a metabolic node orchestrating adipose-hepatic crosstalk in obesity. By linking canonical Wnt signaling to both lipid mobilization and hepatic steatosis, FZD4 emerges as a dual regulator of metabolic homeostasis and a potential therapeutic target for obesity-associated disorders.