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

Abstract

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.

Effects of a methanolic fraction of soybean seeds on the transcriptional activity of peroxisome proliferator-activated receptors (PPAR)

“…Activation of PPARα has been previously demonstrated in several other studies (10,11,12,22). Unexpectedly, however, these fractions in the present study did not induce PPARγ transcriptional activity.…”

“…The well-established beneficial effects of dietary soy on lipid metabolism and insulin sensitivity have been recently attributed to the activation of PPARα and PPARγ, respectively, by soy isoflavones (1,8,10). However, little is known about the possibility that isoflavones activate PPARβ/ δ, which plays a critical role in the regulation of metabolic homeostasis, and also in cardiac lipid metabolism (15,16), fetal development (17), inhibition of human cancer cell line growth (18), protection against liver toxicity (19), modulation of inflammation (6,20), and improved skeletal muscle oxidative enzyme activity in obese patients with type 2 diabetes mellitus (21).…”

“…In contrast to PPARα and PPARγ, the physiological role of PPARβ/δ is not fully known (9). It has been suggested that the anti-inflammatory, antidiabetic and hypolipidemic effects of soy isoflavones may be mediated by activation of PPARα and PPARγ (10)(11)(12). However, little is known about the possibility of activation of PPARβ/δ with soy isoflavones .…”

Can Stevioside in Combination with a Soy-Based Dietary Supplement Be a New Useful Treatment of Type 2 Diabetes? - An in vivo Study in the Diabetic Goto-Kakizaki Rat

“…Vedavanam et al suggested that soy isoflavones may be beneficial for diabetic subjects due to their estrogenic activity and their ability to prevent glucose-induced lipid peroxidation and because they inhibit intestinal glucose uptake by decreasing sodium-dependent glucose transporter, resulting in a reduction of postprandial hyperglycemia [42]. Mezei et al demonstrated that isoflavones improve lipid and glucose metabolism by acting as a PPAR agonist [43]. An isoflavone-containing soy extract doubled PPARdirected gene expression, and a similar induction was observed when the soy isoflavones genistein or daidzein were used to treat cells.…”

Soybean Products Consumption in the Prevention of Cardiovascular Diseases

“…Interestingly, genistein and daidzein, found in soybeans and processed soy protein, have been shown to bind to the peroxisome proliferator-activated receptors (PPAR), particularly to PPAR as well as PPAR and (Dang et al 2003;Mezei et al 2003), suggesting the potential value of isoflavones as a nutritional approach to modulate the action of insulin. PPARs belong to a family of transcription factors of which include three isoforms, PPAR , PPAR ( ) and PPAR .…”