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bioRxiv · 10.64898/2026.03.23.713637

Wnt/β-catenin signaling restrains developmental beiging and imprints long-term energy expenditure

Liu, Z.·Xu, G.·Chen, T.·Zhang, Q.·Zhou, B.·Xue, J.·Xiao, J.·Bai, D.·Chen, Y.·Tian, W.
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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/{beta}-catenin signaling induces a non-canonical Wnt5a-Ca2-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 {beta}-catenin inhibition in both murine and human subcutaneous adipocytes, indicating that Wnt5a-Ca2-AMPK axis is required for the cell-autonomous activation of beige fat. These results reveal Wnt/{beta}-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.

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Liu, Z., Xu, G., Chen, T., Zhang, Q., Zhou, B., Xue, J., Xiao, J., Bai, D., Chen, Y., Tian, W.. 2026-03-27. Wnt/β-catenin signaling restrains developmental beiging and imprints long-term energy expenditure. https://doi.org/10.64898/2026.03.23.713637

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