Identification of a novel agonist of peroxisome proliferator-activated receptors α and γ that may contribute to the anti-diabetic activity of guggulipid in Lep^ob/Lep^ob mice

The ethyl acetate extract of the gum of the guggul tree, Commiphora mukul (guggulipid), is marketed for the treatment of dyslipidaemia and obesity. We have found that it protects Lep^ob/Lep^ob mice from diabetes and have investigated possible molecular mechanisms for its metabolic effects, in particular those due to a newly identified component, commipheric acid. Both guggulipid (EC₅₀=0.82 μg/ml) and commipheric acid (EC₅₀=0.26 μg/ml) activated human peroxisome proliferator-activated receptor α (PPARα) in COS-7 cells transiently transfected with the receptor and a reporter gene construct. Similarly, both guggulipid (EC₅₀=2.3 μg/ml) and commipheric acid (EC₅₀=0.3 μg/ml) activated PPARγ and both promoted the differentiation of 3T3 L1 preadipocytes to adipocytes. Guggulipid (EC₅₀=0.66 μg/ml), but not commipheric acid, activated liver X receptor α (LXRα). E- and Z-guggulsterones, which are largely responsible for guggulipid's hypocholesterolaemic effect, had no effects in these assays. Guggulipid (20 g/kg diet) improved glucose tolerance in female Lep^ob/Lep^ob mice. Pure commipheric acid, given orally (960 mg/kg body weight, once daily), increased liver weight but did not affect body weight or glucose tolerance. However, the ethyl ester of commipheric acid (150 mg/kg, twice daily) lowered fasting blood glucose and plasma insulin, and plasma triglycerides without affecting food intake or body weight. These results raise the possibility that guggulipid has anti-diabetic activity due partly to commipheric acid's PPARα/γ agonism, but the systemic bioavailability of orally dosed, pure commipheric acid appears poor. Another component may contribute to guggulipid's anti-diabetic and hypocholesterolaemic activity by stimulating LXRα.