The fruits of Piper retrofractum Vahl. have been used for their anti-flatulent,
expectorant,
antitussive, antifungal, and appetizing properties in
traditional medicine, and they are reported to possess gastroprotective and
cholesterol-lowering properties. However, their anti-
obesity activity remains unexplored. The present study was conducted to isolate the anti-
obesity constituents from P. retrofractum Vahl. and evaluate their effects in high-fat diet (HFD)-induced obese mice.
Piperidine alkaloids from P. retrofractum Vahl. (PRPAs), including
piperine,
pipernonaline, and
dehydropipernonaline, were isolated as the anti-
obesity constituents through a
peroxisome proliferator-activated receptor δ (PPARδ) transactivation assay. The molecular mechanism was investigated in 3T3-L1 adipocytes and L6 myocytes. PRPA treatment activated
AMP-activated protein kinase (AMPK) signaling and PPARδ
protein and also regulated the expression of lipid metabolism-related
proteins. In the animal model, oral PRPA administration (50, 100, or 300mg/kg/day for 8weeks) significantly reduced HFD-induced
body weight gain without altering the amount of food intake. Fat pad mass was reduced in the PRPA treatment groups, as evidenced by reduced adipocyte size. In addition, elevated serum levels of total
cholesterol,
low-density lipoprotein cholesterol, total
lipid,
leptin, and
lipase were suppressed by PRPA treatment. PRPA also protected against the development of
nonalcoholic fatty liver by decreasing hepatic
triglyceride accumulation. Consistent with the in vitro results, PRPA activated AMPK signaling and altered the expression of lipid metabolism-related
proteins in liver and skeletal muscle. Taken together, these findings demonstrate that PRPAs attenuate HFD-induced
obesity by activating AMPK and PPARδ, and regulate lipid metabolism, suggesting their potential anti-
obesity effects.