Platycodin D, a novel activator of AMP-activated protein kinase, attenuates obesity in db/db mice via regulation of adipogenesis and thermogenesis

Background: Platycodi Radix (root of Platycodon grandiflorum) and its active compound platycodin D (PD) has been previously shown to possess anti-obesity properties, but the underlying mechanisms remain poorly understood. Purpose: The present study was aimed to evaluate the anti-obese effect of PD and reveal its mechanism of action. Study Design/Methods: Genetically obese db/db mice were orally treated with PD for 4 weeks, and body weight gain, adipose tissue weight, serum parameters were measured. Then, assays on adipogenic factors, thermogenic factors, and AMP-activated protein kinase (AMPK) pathway were performed in PD-treated 3T3-L1 murine adi-pocytes, human adipose-derived mesenchymal stem cells (hAMSCs), and primary cultured brown adipocytes. Results: PD treatment attenuated body weight gain, suppressed white adipose tissue weight and improved obesity-related serum parameters in db/db mice. Two major adipogenic factors, peroxisome proliferator-activated receptor gamma (PPAR gamma) and CCAAT/enhancer binding protein alpha (C/EBP alpha) were decreased by PD treatment in WAT of db/db mice, 3T3-L1 adipocytes and hAMSCs. In BAT of db/db mice and primary cultured brown adipocytes, PD treatment elevated the expressions of uncoupled protein 1 (UCP1) and peroxisome pro-liferator-activated receptor gamma coactivator 1 alpha (PCG1 alpha), the key regulators of BAT-associated thermogenesis. In addition, PD activated AMPKa both in vivo and in vitro. However, when AMPK was inhibited by compound C, PD treatment failed to suppress adipogenic factors and increase thermogenic factors. Conclusions: PD improved obesity in db/db mice by AMPK-associated decrease of adipogenic markers including PPAR gamma and C/EBP alpha. PD increased thermogenic factors such as UCP1 and PGC1a in db/db mice and primary cultured brown adipocytes. AMPK inhibition nullified the effects of PD, suggesting its anti-adipogenic and thermogenic actions were dependent on AMPK pathway activation.