Genistein affects adipose tissue deposition in a dose-dependent and gender-specific manner

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 g/kgd) or 17-estradiol (E2) (5 g/kgd) 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 g/kgd 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 6t o 103 26 nM 12 h after treatment and lowered plasma triglycerides and cholesterol levels. The 200,000 g/kgd genistein dose decreased adipose tissue weight similarly to E2. This genistein dose downregulatedestrogenreceptor(morethan)andprogesterone receptorexpressionandinducedestrogen-dependentadipose differentiation factors; it did not change expression of the minimal consensus estrogen-responsive element in ERE-tKLUC 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 g/kgd dose inhibited them. The antiadipogenic action of genistein and down-regulationofadipogenicgenesrequiredtheexpressionofER.In conclusion, nutritional doses of genistein are adipogenic in a gender-specific manner, whereas pharmacological doses inhibited adipose deposition. (Endocrinology 147: 5740–5751, 2006)