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Dietary phytoestrogens activate AMP-activated protein kinase with improvement in lipid and glucose metabolism

From the ¹Department of Genetic Medicine, University of Geneva Medical School
the ²Department of Cellular Physiology and Metabolism, University of Geneva Medical School
the ³Department of Internal Medicine, University of Geneva Medical School, Geneva, Switzerland
the ⁴Institute of Cell Biology, ETH Zürich, Zürich, Switzerland; and
the ⁵National Center for Toxicological Research, Jefferson, Arkansas

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 investigated the mechanisms mediating dietary phytoestrogens actions 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 soy-containing 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 euglycemic-hyperinsulinemic 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 were 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.

Conclusion: Dietary soy could prove useful to prevent obesity and associated disorders. Activation of the AMPK pathway by dietary soy is likely involved and may mediate the beneficial effects of dietary soy in peripheral tissues.

Key Words: Phytoestrogens • isoflavones • dietary soy • obesity • insulin • lipolysis • endocrine disruptors • AMPK • PPAR • PGC-1 • oxidative phosphorylation • reactive oxygen species

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