The ATF3 inducer protects against diet-induced obesity via suppressing adipocyte adipogenesis and promoting lipolysis and browning.

In this study, we investigated whether the activating transcription factor 3 (ATF3) inducer ST32db, a synthetic compound with a chemical structure similar to that of native Danshen compounds, exerts an anti-obesity effect in 3T3-L1 white preadipocytes, D16 beige cells, and mice with obesity induced by a high-fat diet (HFD). The results showed that ST32db inhibited 3T3-L1 preadipocyte differentiation by inhibiting adipogenesis/lipogenesis-related gene (and protein levels) and enhancing lipolysis-related gene (and protein levels) via the activation of β3-adrenoceptor (β3-AR)/PKA/p38, AMPK, and ERK pathways. Furthermore, ST32db inhibited triacylglycerol accumulation in D16 adipocytes by suppressing adipogenesis/lipogenesis-related gene (and protein levels) and upregulating browning gene expression by suppressing the β3-AR/PKA/p38, and AMPK pathways. Intraperitoneally injected ST32db (1 mg kg twice weekly) inhibited body weight gain and reduced the weight of inguinal white adipose tissue (iWAT), epididymal WAT (eWAT), and mesenteric WAT, with no effects on food intake by the obese mice. The adipocyte diameter and area of iWAT and eWAT were decreased in obese mice injected with ST32db compared with those administered only HFD. In addition, ST32db significantly suppressed adipogenesis and activated lipolysis, browning, mitochondrial oxidative phosphorylation, and β-oxidation-related pathways by suppressing the p38 pathway in the iWAT of the obese mice. These results indicated that the ATF3 inducer ST32db has therapeutic potential for reducing obesity.