Constituents from Cistus salvifolius (Cistaceae) Activate Peroxisome Proliferator-Activated Receptor-γ but Not -δ and Stimulate Glucose Uptake by Adipocytes

A number of medicinal/culinary herbs have been reported to improve glucose metabolism and to yield hypoglycemic effects in patients with diabetes. Since stimulation of insulin sensitivity appears to be a potential mechanism, peroxisome proliferator-activated receptor (PPAR) gamma is a likely target molecule for small lipophilic compounds derived from endogenous metabolism and nutrition. Functionally, PPAR gamma integrates the control of energy, lipid, and glucose homeostasis. In addition, PPAR delta activity is involved in energy expenditure. Therefore the aim of this study was to investigate whether PPAR gamma and PPAR delta as well as the stimulation of glucose uptake is activated by botanical products. Cistus salvifolius (Cistaceae) has been identified as a candidate botanical in a preliminary screening of extracts from medicinal plants of Greek flora. In a bioguided approach, crude extracts, fractions and in the end purified compounds have been evaluated for PPAR gamma and PPAR delta specific activities using cell-based transactivation assays. Glucose uptake was measured by nonradioactive 2-[ N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl)amino]-2-deoxyglucose (2-NBDG) uptake. Concerning PPAR gamma several extracts induced reporter gene activity, and clear dose-response patterns (0.1-100 mu g/mL) could be established in the case of the cyclohexane and dichloromethane extracts. Isolation of individual compounds from the cyclohexane extract revealed that at least 6 out of 7 compounds isolated were active with trans-cinnamic acid showing a clear dose-response pattern. In contrast, they were found to be inactive on PPAR delta. The same compounds, however, were also active in stimulating glucose uptake into 3T3-L1 adipocytes. In summary, the bioguided fractionation of Cistus salvifolius yields PPAR gamma stimulating metabolites with differing chemical natures. In conclusion, PPAR gamma represents a candidate molecule for the mediation of improvement of glucose metabolism by botanical/nutritional products.