Brown adipocyte-derived SAA3-CPT1A axis regulates diet-induced thermogenesis and protects against obesity

Diet-induced thermogenesis (DIT), a critical component of energy expenditure driven by brown adipose tissue (BAT), is essential for maintaining metabolic health; however, its precise molecular regulation remains poorly understood. We investigated whether serum amyloid A3 (SAA3), a factor secreted by brown adipocytes, regulates DIT and protects against diet-induced obesity. Using two distinct mouse models: mice with brown adipocyte-specific Saa3 deletion and mice with lentiviral-mediated Saa3 overexpression in BAT, we examined energy expenditure, substrate utilization, and thermogenic responses under chow or short-term high-fat diet feeding. SAA3 expression in BAT was acutely induced by refeeding. Loss of SAA3 severely diminished postprandial DIT and total energy expenditure, leading to accelerated weight gain on a high-fat diet. Mechanistically, Saa3 deletion compromised uncoupling protein‑1 induction, chiefly by impairing adipose triglyceride lipase-driven lipolysis and, critically, by inhibiting carnitine palmitoyltransferase 1A (CPT1A)-dependent fatty acid oxidation (FAO). Conversely, SAA3 overexpression robustly enhanced DIT, stimulated lipolysis and FAO, and promoted mitochondrial oxidative phosphorylation. Studies in primary brown adipocytes confirmed that SAA3 deficiency reduced CPT1A expression, palmitate-stimulated lipolysis, and mitochondrial respiration. Together, these findings identify the SAA3-CPT1A axis as a novel, BAT-intrinsic mechanism that couples nutrient sensing to uncoupling protein‑11 function via enhanced FAO. By promoting lipid utilization and postprandial energy dissipation, SAA3 optimizes postprandial thermogenesis and defends against obesity, highlighting conserved SAA signaling as a potential nutritional and therapeutic target in metabolic disease.