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

Abstract

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) γ is a likely target molecule for small lipophilic compounds derived from endogenous metabolism and nutrition. Functionally, PPARγ integrates the control of energy, lipid, and glucose homeostasis. In addition, PPARδ activity is involved in energy expenditure. Therefore the aim of this study was to investigate whether PPARγ and PPARδ 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 PPARγ and PPARδ 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 PPARγ several extracts induced reporter gene activity, and clear dose-response patterns (0.1–100 µg/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 PPARδ. The same compounds, however, were also active in stimulating glucose uptake into 3T3-L1 adipocytes. In summary, the bioguided fractionation of Cistus salvifolius yields PPARγ stimulating metabolites with differing chemical natures. In conclusion, PPARγ represents a candidate molecule for the mediation of improvement of glucose metabolism by botanical/nutritional products.

Cistus salvifolius - Cistaceae - PPARγ transactivation - glucose uptake - adipocytes

References

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1 Both authors contributed equally.