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Genistein Affects Adipose Tissue Deposition in a Dose-Dependent and Gender-Specific Manner

Third Laboratory/Biotechnology (M.P., C.M., D.D.L.) and Department of Diagnostics, Civic Hospital of Brescia, 25123 Brescia, Italy; Department of Pathology (P.G.G.) and Divisions of Gynecologic Oncology (E.B.) and Statistic and Biometry (S.C.), University of Brescia, 25123 Brescia, Italy; E. Menni Research Center (O.P.), Poliambulanza, 25124 Brescia, Italy; Instituto de Bioingeniería (P.A.-M., A.N.), Universidad Miguel Hernández de Elche, Elche 03202, Alicante Spain; Center of Excellence on Neurodegenerative Diseases (L.O., A.M.), University of Milan, 20133 Milan, Italy; and Departments of Internal Medicine (B.P., A.T., M.L.B.) and Pharmacological Sciences (A.R., P.V.), University of Florence, 50121 Florence, Italy

Address all correspondence and requests for reprints to: Diego Di Lorenzo, 3rd Laboratory/Biotechnology, Civic Hospital of Brescia, 25123 Brescia, Italy. E-mail: dilorenzodiego{at}yahoo.it.

The soy isoflavone genistein targets adipose tissue and elicits physiological effects that may vary based on dietary intake. We hypothesized that the adipose effects of genistein are dose and gender dependent. Four-week-old C57BL/6 male and female mice received daily oral doses of genistein (50–200,000 µg/kg·d) or 17ß-estradiol (E2) (5 µg/kg·d) for 15 d or a diet containing 800 ppm genistein. Genistein increased epididymal and renal fat pad and adipocyte size at doses up to 50,000 µg/kg·d or at 800 ppm in the diet in males but not in females. The alteration in adipocity correlated with changes in peripheral insulin resistance. These treatments increased genistein serum concentrations from 35 ± 6 to 103 ± 26 nM 12 h after treatment and lowered plasma triglycerides and cholesterol levels. The 200,000 µg/kg·d genistein dose decreased adipose tissue weight similarly to E2. This genistein dose down-regulated estrogen receptor (ß more than ) and progesterone receptor expression and induced estrogen-dependent adipose differentiation factors; it did not change expression of the minimal consensus estrogen-responsive element in ERE-tK-LUC mice, which was positively modulated in other tissues (e.g. the lung). E2 down-regulated almost all examined adipogenic factors. Gene microarray analysis identified factors in fat metabolism and obesity-related phenotypes differentially regulated by low and high doses of genistein, uncovering its adipogenic and antiadipogenic actions. The lower dose induced the phospholipase A2 group 7 and the phospholipid transfer protein genes; the 200,000 µg/kg·d dose inhibited them. The antiadipogenic action of genistein and down-regulation of adipogenic genes required the expression of ERß. In conclusion, nutritional doses of genistein are adipogenic in a gender-specific manner, whereas pharmacological doses inhibited adipose deposition.

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