Dietary Phytoestrogens Activate AMP-Activated Protein Kinase With Improvement in Lipid and Glucose Metabolism
Christopher R. Cederroth 1 ,
Manlio Vinciguerra 2 ,
Asllan Gjinovci 2 ,
Françoise Kühne 1 ,
Marcella Klein 3 ,
Manon Cederroth 1 ,
Dorothée Caille 2 ,
Mariane Suter 4 ,
Dietbert Neumann 4 ,
Richard W. James 5 ,
Daniel R. Doerge 6 ,
Theo Wallimann 4 ,
Paolo Meda 2 ,
Michelangelo Foti 2 ,
Françoise Rohner-Jeanrenaud 3 ,
Jean-Dominique Vassalli 1 and
Serge Nef 1
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
Abstract
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.
ACC, acetyl-CoA carboxylase
AMPK, AMP-activated protein kinase
AUC, area under curve
DEXA, dual-energy X-ray absorptiometry
ER, estrogen receptor
ERRα, estrogen receptor–related receptor α
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 γ co-activator
PPAR, peroxisome proliferator–activated receptor
ROS, reactive oxygen species
TG, triglyceride
WAT, white adipose tissue
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on day month year. DOI: 10.2337/db07-0630.
Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0630 .
The costs of publication of this article were defrayed in part by the payment of page charges. This article must t...

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

10.2337/db07-0630