Wnt/β-catenin signaling restrains developmental beige adipocyte thermogenesis and its inhibition imprints long-term energy expenditure

Abstract Beige adipocytes that emerge during the peri-weaning period support sympathetic nervous system (SNS)-independent thermogenesis, yet the mechanisms governing this spontaneous beiging remain unclear. Here, by integrating transcriptomic profiling with adipocyte-targeted Ctnnb1 deletion in mice, we identify the canonical Wnt signaling as an endogenous brake on developmental beige thermogenesis. Peri-weaning inguinal fat from adipocyte Ctnnb1 knockout mice exhibits enhanced beige adipocyte biogenesis, with increased thermogenesis-related gene expression and mitochondrial oxidative capacity, which programs durable activation of adaptive thermogenesis and augmented whole-body energy expenditure into adulthood. Mechanistically, suppression of Wnt/β-catenin signaling induces a non-canonical Wnt5a-Ca 2 ⁺-AMPK axis that promotes triglyceride lipolysis and subsequent PPAR-driven fatty acid oxidation, thereby fueling mitochondrial respiration. Genetic or pharmacological disruption of this axis blunts thermogenic responses induced by β-catenin inhibition in both murine and human subcutaneous adipocytes, indicating that Wnt5a-Ca 2 ⁺-AMPK axis is required for the cell-autonomous activation of beige fat. These results reveal Wnt/β-catenin signaling as a developmental constraint on beige adipocyte formation and suggest an SNS-independent route to sustainably raise energy expenditure and improve metabolic health.