Lifelong exposure to dietary isoflavones reduces risk of obesity in ovariectomized Wistar rats.

SCOPE: Traditional Asian diet rich in soy isoflavones (ISOs) is discussed to be linked to a lower obesity prevalence. In lifelong and short-term exposure scenarios we investigated effects of an ISO-rich diet on the body composition and development of obesity in female rats. METHODS AND RESULTS: Female Wistar rats grew up on ISO-free or ISO-rich control diet (CON ISO: 467 mg/kg diet). Starting postnatal day 83, ovariectomized and intact animals received high calorie Western diet (WD) in the absence or presence of ISO (WD ISO: 431 mg/kg diet) for 12 weeks to induce obesity or maintained on respective control diet (CON). One group starting ISO exposure after ovariectomy mimics short-term ISO exposure in postmenopausal Western women. Lifelong but not short-term ISO exposure resulted in reduced body weight, visceral fat mass, serum leptin, and smaller adipocytes. ISO decreased hepatic SREBP-1c, ACC, FAS, and PPARγ mRNA expression in nonobese animals. Moreover, ovariectomy reduced skeletal muscle weight, which was antagonized by both short-term and lifelong ISO exposure. CONCLUSION: Our results indicate that in female rats lifelong but not short-term ISO intake reduces the risk to develop obesity. Furthermore, lifelong and short-term ISO exposure may antagonize loss of skeletal muscle mass induced by ovariectomy.

Dose-dependent effects of isoflavone exposure during early lifetime on the rat mammary gland: Studies on estrogen sensitivity, isoflavone metabolism, and DNA methylation.

SCOPE: Isoflavone (ISO) exposure during adolescence modulates 17ß-estradiol (E2) sensitivity of the adult mammary gland. The present study investigated the dose dependency of these effects focusing on proliferation, estrogen receptor dependent and independent gene expression, as well as DNA methylation and ISO metabolism. METHODS AND RESULTS: Female Wistar rats were lifelong exposed to an ISO-depleted diet or to diets enriched with a soy ISO extract (ISO-rich diet (IRD)) causing plasma concentrations as observed minimally (IRDlow) and maximally (IRDhigh) in Asian women. The extract was characterized by both phytochemical analysis and E-Screen. Rats were ovariectomized at postnatal day (PND) 80 and treated with E2 from PND94 to 97. In contrast to uterine response, body weight and visceral fat mass were affected by ISO. In the mammary gland, both E2-induced proliferation (proliferating cell nuclear antigen staining) and estrogen receptor activation (progesterone receptor staining) were significantly reduced by IRDhigh but not by IRDlow, which however attenuated Gdf15 mRNA expression. DNA methylation analysis revealed significant differences in the promoter regions of Aldhl1, Extl1, and WAP between IRDhigh and ISO-depleted diet. CONCLUSION: Lifelong exposure to ISO results in dose-dependent differential effects on proliferation, gene expression, and DNA methylation in rat mammary glands. Yet, a decrease in estrogen responsiveness was only achieved by IRDhigh.

Aging is associated with a shift of fatty metabolism toward lipogenesis.

The incidence of nonalcoholic fatty liver disease is steadily increasing among the elderly population. Lipid metabolism is transcriptionally controlled by the nuclear receptors retinoid acid receptor alpha, liver-X-receptor alpha, and peroxisome proliferator-activated receptor alpha and their target genes ABCA1, sterol regulatory element-binding protein-1c, and fatty acid synthase. Using senescence-accelerated prone mice (SAMP8), we addressed the question as to whether age-related increase of oxidative stress affects nuclear receptor gene expression. In contrast to SAMR1 control mice, young SAMP8 mice exhibit hepatic steatosis with increased hepatic cholesterol content, plasma triglyceride, and aspartate aminotransferase levels. This is accompanied by an increase of liver-X-receptor alpha and retinoid acid receptor alpha expression, whereas peroxisome proliferator-activated receptor alpha expression is found diminished. SAMP8 mice further reveal a lower expression of ABCA1 as well as of sterol regulatory element-binding protein-1c and higher expression of fatty acid synthase. The dysbalance between the nuclear receptors and their target genes most probably mediates hepatic steatosis and underlines the pathological relevance of nuclear receptor shift toward lipogenesis in fat metabolism of the elderly patient.