Cold-induced serum amyloid A3 amplifies cAMP-PKA signaling to drive adaptive thermogenesis in brown adipocytes.

Serum amyloid A3 (SAA3) is typically associated with inflammation, but its role in brown adipose tissue (BAT) thermogenesis remains elusive. Here, we identify SAA3 as a cold-inducible, locally acting amplifier of BAT thermogenesis. Using lentiviral modulation and BAT-specific knockout mice, we demonstrate that SAA3 is essential for cold tolerance and energy expenditure. Mechanistically, secreted SAA3 augments thermogenic signaling via a GPR3-dependent cAMP/PKA axis, driving robust UCP1 induction. Notably, this activation triggers transcriptional upregulation of endogenous Saa3 and Gpr3, establishing an autocrine/paracrine amplification loop that accelerates thermogenic output. Consequently, SAA3 loss blunts thermogenic responses in vivo and in vitro. These findings establish SAA3 as a BAT-derived regulator linking cold exposure to energy dissipation via a GPR3-mediated mechanism, highlighting its therapeutic potential for metabolic diseases.