CCRL2 deficiency inhibits thermogenesis in mice by altering macrophage polarization

Obesity is a global health challenge driven by excessive fat accumulation and disrupted energy homeostasis. While white adipose tissue (WAT) stores energy, brown adipose tissue (BAT) and beige fat mediate thermogenesis. Enhancing WAT browning is a promising anti-obesity strategy. In this study, we demonstrate that C-C motif chemokine receptor-like 2 (CCRL2) deficiency promotes macrophage polarization toward a pro-inflammatory M1 phenotype. This shift inhibits the cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) thermogenic signaling axis in subcutaneous WAT (sWAT), subsequently suppressing uncoupling protein 1 (UCP1) expression and browning capacity. Notably, this thermogenic impairment occurs independently of the classical β-adrenergic receptor pathway. Interestingly, we observed elevated p38 MAPK phosphorylation despite reduced thermogenesis, suggesting a novel non-adrenergic regulatory mechanism driven by macrophage-adipocyte crosstalk. Our findings identify CCRL2 as a critical immune checkpoint regulating adipose tissue thermogenesis and suggest it as a potential therapeutic target for obesity and related metabolic disorders.