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Dietary Phytoestrogens Activate AMP-Activated Protein Kinase With Improvement in Lipid and Glucose Metabolism

¹ Department of Genetic Medicine and Development and National Centre of Competence in Research–Frontiers in Genetics, University of Geneva, Geneva, Switzerland
² Department of Cellular Physiology and Metabolism, Faculty of Medicine, University of Geneva, Geneva, Switzerland
³ Laboratory of Metabolism, University of Geneva, Geneva, Switzerland
⁴ Institute of Cell Biology, ETH Zürich, Zürich, Switzerland
⁵ Clinical Diabetes Unit, Division of Endocrinology, Diabetology, and Nutrition, Faculty of Medicine, Department of Internal Medicine, University of Geneva, Geneva, Switzerland
⁶ National Center for Toxicological Research, Jefferson, Arkansas

Corresponding author: Serge Nef, Department of Genetic Medicine and Development and National Centre of Competence in Research–Frontiers in Genetics, University of Geneva, 1211 Geneva 4, Switzerland. E-mail: serge.nef{at}medecine.unige.ch

Abbreviations: ACC, acetyl-CoA carboxylase; AMPK, AMP-activated protein kinase; AUC, area under curve; DEXA, dual-energy X-ray absorptiometry; ER, estrogen receptor; ERR, estrogen receptor–related receptor ; FFA, free fatty acid; GLP-1, glucagon-like peptide 1; GTT, glucose tolerance test; HPLC, high-performance liquid chromatography; IRβ, insulin receptor β; IRS, insulin receptor substrate; ITT, insulin tolerance test; mAb, monoclonal antibody; mTOR, mammalian target of rapamycin; PGC, peroxisome proliferator–activated receptor co-activator; PPAR, peroxisome proliferator–activated receptor; ROS, reactive oxygen species; TG, triglyceride; WAT, white adipose tissue

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 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 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.

CONCLUSIONS— 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.

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