OBJECTIVE-Emerging evidence suggests that dietary phytoestrogens can have beneficial effects on obesity and diabetes, although their mode of action is not known. Here, we investigate the mechanisms mediating the action of dietary phytoestrogens on lipid and glucose metabolism in rodents.RESEARCH DESIGN AND METHODS-Male CD-1 mice were fed from conception to adulthood with either a high soycontaining diet or a soy-free diet. Serum levels of circulating isoflavones, ghrelin, leptin, free fatty acids, triglycerides, and cholesterol were quantified. Tissue samples were analyzed by quantitative RT-PCR and Western blotting to investigate changes of gene expression and phosphorylation state of key metabolic proteins. Glucose and insulin tolerance tests and euglycemichyperinsulinemic clamp were used to assess changes in insulin sensitivity and glucose uptake. In addition, insulin secretion was determined by in situ pancreas perfusion.RESULTS-In peripheral tissues of soy-fed mice, especially in white adipose tissue, phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase was increased, and expression of genes implicated in peroxisomal fatty acid oxidation and mitochondrial biogenesis was upregulated. Soy-fed mice also showed reduced serum insulin levels and pancreatic insulin content and improved insulin sensitivity due to increased glucose uptake into skeletal muscle. Thus, mice fed with a soy-rich diet have improved adipose and glucose metabolism. A better understanding of the factors regulating lipid and glucose metabolism are of eminent interest due to the pandemic development of obesity and its related metabolic disorders. Preventive strategies to control excess body weight and insulin resistance have mainly focused on physical exercise and total caloric intake. Over the past years, however, an increasing body of evidence indicates that estrogens are important regulators of glucose and adipose metabolism. They are known to modulate the distribution of body fat and adipose tissue metabolism either through the direct regulation of adipogenesis and lypolysis or indirectly via modulation of the energy balance (rev. in 1). Similarly, estrogens play an important role in glucose homeostasis and are known to modulate insulin sensitivity (2). Postmenopausal women develop visceral obesity and insulin resistance and are at an increased risk for diabetes; estrogen replacement therapy normalizes these abnormalities (3,4). In rodent models of type 2 diabetes, female mice are protected against hyperglycemia unless they are ovariectomized, whereas in male animals, estrogen perfusion reverses diabetes (5). Finally, estrogen receptor (ER)␣ or aromatase-knockout mice display several phenotypes associated with the metabolic syndrome, such as increased adiposity, glucose intolerance, and insulin resistance (6,7), demonstrating the fundamental implication of estrogens in these metabolic processes. CONCLUSIONS-DietaryPhytoestrogens are nonsteroidal compounds of natural origin that can bind to both ER␣ and ER␤ and ...

Despite extensive studies, the hematopoietic versus hepatic origin of liver progenitor oval cells remains controversial. The aim of this study was to determine the origin of such cells after liver injury and to establish an oval cell line. Rat liver injury was induced by subcutaneous insertion of 2-AAF pellets for 7 days with subsequent injection of CCl 4 . Livers were removed 9 to 13 days post-CCl 4 treatment. Immunohistochemistry was performed using anti-c-kit, OV6, Thy1, CK19, AFP, vWF and Rab3b. Isolated non-parenchymal cells were grown on mouse embryonic fibroblast, and their gene expression profile was characterized by RT-PCR. We identified a subpopulation of OV6/CK19/Rab3b-expressing cells that was activated in the periportal region of traumatized livers. We also characterized a second subpopulation that expressed the HSCs marker c-kit but not Thy1. Although we successfully isolated both cell types, OV6/CK19/Rab3b + cells fail to propagate while c-kit + -HSCs appeared to proliferate for up to 7 weeks. Cells formed clusters which expressed c-kit, Thy1 and albumin. Our results indicate that a bona fide oval progenitor cell population resides within the liver and is distinct from c-kit + -HSCs. Oval cells require the hepatic niche to proliferate, while cells mobilized from the circulation proliferate and transdifferentiate into hepatocytes without evidence of cell fusion.