Baicalein alleviates Western diet-induced obesity via metabolically activated adipose tissue macrophages by inducing...

Western diet (WD)-induced obesity is closely associated with dysfunctional adipose tissue macrophages (ATMs), particularly the metabolically activated macrophages (MMe) and the impairment of lysosomal function. Baicalein, a natural flavonoid, has been reported to exert anti-obesity effects. However, its impact on the MMe phenotype of ATMs and the underlying mechanisms remain unclear. Here, we investigated the role of Nrf2 in baicalein-mediated ATM regulation using both genetic and pharmacological tools: myeloid-specific Nrf2 knockout mice (Nrf2^MKO) in vivo and the Nrf2-specific inhibitor ML385 in MMe-polarized RAW264.7 macrophages treated with baicalein in vitro. Baicalein treatment for 16 weeks reduced body weight, adipose tissue mass, and improved dyslipidemia in WD-induced obese mice. This was accompanied by reduced formation of CLS and elevated expression of lysosomal genes (Lamp2, Lal) in ATMs. In Nrf2^MKO mice, baicalein's effects on body weight and fat mass were largely abolished, while its inhibitory effect on adipocyte hypertrophy was preserved. Myeloid Nrf2 ablation impaired ATM MMe polarization and lysosomal function, which were partially restored by baicalein. In vitro, baicalein activated Nrf2, upregulated MMe markers (CD36, Plin2, Abca1) and lysosomal genes (Lamp2, Lal), and reduced lipid accumulation in MMe-polarized RAW264.7 macrophages, all of which were blocked by ML385. Collectively, our findings establish that baicalein alleviates obesity by activating Nrf2 to enhance lysosomal function and promote MMe polarization of ATMs, highlighting Nrf2 as a key regulator and therapeutic target in MMe-polarized ATMs and identifying baicalein as a promising anti-obesity candidate.