Soy Isoflavones Exert Antidiabetic and Hypolipidemic Effects Through the PPAR Pathways in Obese Zucker Rats and Murine RAW 264.7 Cells

The hypocholesterolemic and anti-atherosclerotic mechanism by which soy may exert a beneficial effect remains unclear. Peroxisome-proliferator activated receptors (PPAR) are promiscuous nuclear receptors that regulate the transcription of genes involved in lipid and glucose homeostasis and lipid metabolism within the cell. We hypothesize that the isoflavones improve lipid and glucose metabolism by acting as an antidiabetic PPAR agonist. Male and female obese Zucker rats (OZR) were used as a model of Type 2 diabetes, and OZR fed a high isoflavone soy protein diet displayed improvements in lipid metabolism consistent with results in humans treated with antidiabetic PPAR agonists such as the fibrates or glitazones. Liver triglyceride and cholesterol concentrations were lower in all OZR fed high-isoflavone soy protein diets than in rats fed low-isoflavone and casein diets (P < 0.05). Concurrently, PPAR-directed gene expression was evaluated in a cell culture model. An isoflavone-containing soy extract doubled PPAR-directed gene expression (P < 0.05) in RAW 264.7 cells containing either a PPARalpha or PPARgamma expression plasmid. A similar induction was observed when the soy isoflavones genistein or daidzein were used to treat cells. Both isoflavones doubled PPARalpha-directed gene expression (P < 0.05), whereas they increased PPARgamma-directed gene expression 200-400% (P < 0.05). This study suggests that soy isoflavones improve lipid metabolism, produce an antidiabetic effect, and activate PPAR receptors.