Amorfrutins are potent antidiabetic dietary natural products

Given worldwide increases in the incidence of obesity and type 2 diabetes, new strategies for preventing and treating metabolic diseases are needed. The nuclear receptor PPAR. (peroxisome proliferator-activated receptor gamma) plays a central role in lipid and glucose metabolism; however, current PPAR.-targeting drugs are characterized by undesirable side effects. Natural products from edible biomaterial provide a structurally diverse resource to alleviate complex disorders via tailored nutritional intervention. We identified a family of natural products, the amorfrutins, from edible parts of two legumes, Glycyrrhiza foetida and Amorpha fruticosa, as structurally new and powerful antidiabetics with unprecedented effects for a dietary molecule. Amorfrutins bind to and activate PPAR., which results in selective gene expression and physiological profiles markedly different from activation by current synthetic PPAR. drugs. In diet-induced obese and db/db mice, amorfrutin treatment strongly improves insulin resistance and other metabolic and inflammatory parameters without concomitant increase of fat storage or other unwanted side effects such as hepatoxicity. These results show that selective PPAR.-activation by diet-derived ligands may constitute a promising approach to combat metabolic disease.