Saponins from <i>Panax japonicus</i> Enhance Lipolysis via Acting on FGF21-β-Klotho/FGFR1 in Obese Mice

Saponins from <i>Panax japonicus</i> (SPJ) had a significant antiobesity action, and fibroblast growth factor 21 (FGF21) plays a central role in energy, lipid, and glucose homeostasis. We explored whether FGF21 is the target site of SPJ in lipolysis to improve lipid metabolism. We established an obese mouse model that was fed with a high-fat diet (HFD) for 16 weeks, and these obese mice were medicated with low-dose SPJ (15 mg/kg) or high-dose SPJ (45 mg/kg). The effects of SPJ on lipid metabolism, particularly on sympathetic activation and subsequent lipolysis in white adipose tissue (WAT), were evaluated. Furthermore, the impacts of SPJ on adipose FGF21 and its receptors β-Klotho (KLB) and FGFR1 within the central nervous system (CNS) were examined. Then, we observed the actions of FGF21 on WAT lipolysis as well as on KLB and FGFR1 within the CNS. Our results showed that SPJ treatment ameliorated lipid metabolism and protected against chronic HFD-induced obesity in a dose-independent manner. In WATs of HFD-induced obese mice, SPJ stimulated sympathetic innervation and enhanced lipolysis by increasing the expressions of FGF21 and its receptors (KLB and FGFR1). Moreover, SPJ had the capability to activate KLB- and FGFR1-expressing neurons in the paraventricular nucleus (PVN) of the hypothalamus and area postrema (AP)/nucleus tractus solitarius (NTS) of the HFD-induced obese mice. Interestingly, FGF21 analogue treatment partly recapitulated the action of SPJ on lipid metabolism by enhancing sympathetic activation and lipolysis in WATs of the HFD-induced obese mice. Like SPJ, FGF21 analogue treatment also activated KLB- and FGFR1-expressing neurons in PVN and AP/NTS. This study demonstrated that SPJ acted on adipose FGF21 and brain KLB/FGFR1 in obese mice to enhance sympathetic innervation and lipolysis, contributing to improved lipid metabolism.