coumestrol and Body-Weight

Coumestrol is a dietary phytoestrogen with estrogen-mimicking characteristics. This study investigated the molecular mechanisms of antiobesity effects of coumestrol. Two weeks of coumestrol treatment reduced body weight and improved glucose tolerance of high-fat diet (HFD)-fed mice. Notably, coumestrol treatment reduced adiposity but expanded brown adipose tissue mass. In addition, coumestrol treatment induced up-regulation of brown adipocyte markers and lipolytic gene expression in adipose tissue. Mechanistically, coumestrol induced an increase in mitochondrial contents of brown adipose tissue, which was associated with up-regulation of adenosine monophosphate-activated protein kinase and sirtuin 1. In vitro knockdown of estrogen receptor 1 inhibited the effect of coumestrol on brown adipogenic marker expression, increase in mitochondrial contents and oxygen consumption rate in brown adipocytes. Furthermore, lineage tracing of platelet-derived growth factor receptor A-positive (PDGFRA+) adipocyte progenitors confirmed increased levels of de novo brown adipogenesis from PDGFRA+ cells by coumestrol treatment. In conclusion, our results indicate that coumestrol has antiobesity effects through the expansion and activation of brown adipose tissue metabolism.

Topics: Adipocytes, Beige; Adipogenesis; Adipose Tissue, Brown; Adipose Tissue, White; Adiposity; Animals; Body Weight; Coumestrol; Diet, High-Fat; Glucose Tolerance Test; Lipolysis; Male; Mice; Mice, Inbred C57BL; Obesity; Phytoestrogens

There is a great deal of controversy surrounding the issue of hormone replacement therapy after transplantation. The question whether or not this therapy has effects in cardiac allograft vasculopathy (CAV), the Achilles heel of cardiac transplantation or other unique aspects of allograft function is still unknown.. We investigated the long-term effect of 17beta-estradiol as well as phytoestrogen Coumestrol, a synthetically produced phytoestrogen, on the development of CAV and the degree of fibrosis in an ovariectomized female heterotopic chronic allograft model (LEW-F344).. We found that, 150 days after transplantation, no significant effect of estrogen application on intimal thickening of coronary arteries was observed. 17beta-estradiol and phytoestrogen Coumestrol did significantly reduce the perivascular immune reaction. However, the immune effect had no consequence on the intensity of CAV. Although neither 17beta-estradiol nor phytoestrogen Coumestrol revealed a positive effect on CAV, the group of animals treated with 17beta-estradiol showed the highest decline in heart function and the most distinct fibrosis.. 17beta-estradiol does not affect CAV positively, but worsens cardiac allograft function and leads to increased fibrosis. This is the first study showing a negative effect of 17-beta-estradiol after heart transplantation in the long term.

Topics: Animals; Body Weight; Coumestrol; Disease Models, Animal; Estradiol; Female; Heart Transplantation; Phytoestrogens; Postoperative Complications; Rats; Rats, Inbred F344; Rats, Inbred Lew; T-Lymphocytes; Transplantation, Homologous; Transplantation, Isogeneic; Uterus; Weight Gain

The neural control systems for the ovulatory cycle and lordosis behavior are sexually differentiated by estrogen during the perinatal period in rats. In the present study, the effects of a single neonatal injection with the phytoestrogen, coumestrol, on female reproductive functions were investigated. Female rats were injected subcutaneously with 1 or 3mg coumestrol (CM1, CM3), 1mg genistein (GS1), 1mg estradiol (E2), or oil at day 5 after birth (birth day=day 1) and an estrous cycle check and lordosis behavior test were performed. As a result, vaginal opening was advanced in CM1-, CM3- or E2-treated females. A vaginal smear check indicated that oil- or GS1-treated females showed a constant 4- or 5-day estrous cycle, whereas CM1-, CM3- or E2-treated rats showed a persistent or prolonged estrus. Ovariectomy was performed in all females at 60 days of age. The ovary weights in the CM1-, CM3- or E2-treated groups were lower than those in the oil- and GS1-treated groups and no corpora lutea were found in any rats of these three groups, except for two E2-treated rats. Behavioral tests were carried out after implantation of E2-tubes. All rats in the CM1-, GS1-treated groups showed a high lordosis quotient (LQ), being comparable to that in the oil-treated females. On the other hand, LQs in the CM3, E2 or male groups were lower than that in the control female group. These results suggest that a single neonatal injection of 3 mg coumestrol was effective in suppressing the functions of ovulation-inducing mechanisms and the induction of lordosis, but 1mg coumestrol was effective in only the estrous cycle of female rats.

Topics: Animals; Animals, Newborn; Behavior, Animal; Body Weight; Contraceptives, Oral, Combined; Coumestrol; Dose-Response Relationship, Drug; Estradiol; Estrous Cycle; Ethynodiol Diacetate; Female; Male; Mestranol; Organ Size; Ovariectomy; Phytoestrogens; Posture; Pregnancy; Rats; Rats, Wistar; Sexual Behavior, Animal; Time Factors; Vagina

The cyclic siloxane octamethylcyclotetrasiloxane (D4) and the linear siloxane hexamethyldisiloxane (HMDS) have numerous industrial and consumer applications and thus have the potential for human exposure. The present study was undertaken to examine potential estrogenic and antiestrogenic activities of D4 and HMDS. To address potential differences in sensitivity between rat strains the study used both Sprague-Dawley (SD) and Fischer 344 (F-344) rats. Estrogenicity of the test compounds was determined by measuring absolute and relative uterine weights in immature rats and by monitoring uterine epithelial cell height. In order to place the data obtained for D4 into perspective relative to strong and weak estrogenic compounds, the response produced by D4 at 0, 10, 50, 100, 250, 500, and 1000 mg/kg/day was compared to responses produced by ethinyl estradiol (EE) (1, 3, 10, or 30 microg/kg/day), diethylstilbestrol dipropionate (DES-DP) (0.5, 1.5, 5, 15 microg/kg/day), and coumestrol (CE) (10, 35, 75, 150 mg/kg/day). Antiestrogenic effects were evaluated by co-administering D4 (500 mg/kg/day) with EE at 1, 3, 10, and 30 microg /kg/day. All compounds were administered in sesame oil at a volume of 5 mL/kg by oral gavage. Beginning on postnatal day 18 (SD) or 21 (F-344) each pup (12 per group) received a single dose of test compound once a day for 4 consecutive days. The pups were euthanized the morning after the last treatment and their uteri removed, weighed, and processed for histological examination. EE and DES-DP produced a significant dose-dependent increase in absolute and relative uterine weights and uterine cell height. The maximum increase in uterine weight following EE exposure was approximately 350% relative to controls in both strains. The weak phytoestrogen CE also produced a dose-related increase in absolute and relative uterine weight and epithelial cell height, but the response occurred over a much higher range of doses. At the highest dose of CE, uterine weight was increased approximately 230% relative to controls. Following exposure to D4, absolute and relative uterine weights and uterine epithelial cell height were statistically significantly increased in both strains of rats at doses above 100 mg/kg/day. In terms of uterine weight, D4 was approximately 0.6 million times less potent than EE or DES-DP in SD pups and 3.8 million times less potent than EE or DES-DP in F-344 pups. The maximal increase in uterine weight, relative to controls, produce

Topics: Administration, Oral; Animals; Biological Assay; Body Weight; Coumestrol; Diethylstilbestrol; Dose-Response Relationship, Drug; Estrogen Antagonists; Estrogens, Non-Steroidal; Ethinyl Estradiol; Female; Rats; Rats, Inbred F344; Rats, Sprague-Dawley; Siloxanes; Species Specificity; Uterus

The effects of a phytoestrogen diet on sexual differentiation were examined in lactationally exposed rat pups. Rat dams were provided a semipurified diet containing the isoflavonoid coumestrol at a concentration (0.01%) previously found to be uterotrophic. Coumestrol treatment did not significantly alter the time of vaginal opening, although vaginal opening did occur at a lighter body weight. By 132 days of age, 83% of coumestrol-treated females exhibited the cornified smears of a persistent estrous state. By contrast, 91% of control animals were cycling regularly at 132 days of age. Estradiol stimulation failed to elicit an LH elevation in the coumestrol-treated animals, suggesting the possibility of neuroendocrine impairments. These findings indicate that the female offspring of mothers fed a low-level phytoestrogen diet during lactation manifest early and nearly universal disruption of cyclicity of the persistent-estrus type.

Topics: Animals; Anovulation; Body Weight; Coumestrol; Diet; Eating; Estrogens; Estrogens, Non-Steroidal; Female; Isoflavones; Lactation; Luteinizing Hormone; Phytoestrogens; Plant Preparations; Plants, Edible; Pregnancy; Rats; Rats, Sprague-Dawley; Sexual Maturation; Syndrome

The study reported here examined the effects of a phytoestrogen diet on progestin receptor induction, vaginal opening, and the onset and maintenance of vaginal cycles in developing female rats. A natural dietary concentration (0.01%) of the isoflavonoid coumestrol was incorporated into the AIN semipurified diet and fed from 21 to 24 days (acute treatment) or from 22 to 60 days (chronic treatment). Progestin receptor induction was observed in the uterus, pituitary, and hypothalamus-preoptic area following acute treatment. Responses were more marked in the uterus and pituitary than in the hypothalamus-preoptic area. Vaginal opening was accelerated by 4 days during chronic coumestrol treatment and occurred at a lighter body weight. Vaginal cycles began on vaginal opening and did not differ in regularity from those of control animals. However, irregular cycles were observed in coumestrol-treated animals at 116 to 131 days, suggesting that chronic coumestrol treatment may have induced some permanent changes in reproductive function. These findings demonstrate that plant estrogens, at natural dietary levels, produce significant, agonistic actions in several estrogen-dependent tissues and processes.

Topics: Analysis of Variance; Animals; Body Weight; Coumestrol; Diet; Estrogens; Estrus; Female; Hypothalamus; Pituitary Gland; Rats; Rats, Inbred Strains; Receptors, Progesterone; Reproduction; Uterus; Vagina

This study used the neonatal mouse model to determine if early exposure of female mice to coumestrol, a plant estrogen, would result in reproductive-tract alterations similar to those seen after neonatal exposure to diethylstilbestrol (DES). Newborn female C57BL/Crgl mice were given daily subcutaneous injections of 0.08 micrograms DES or 100 micrograms coumestrol in 0.005 ml dimethyl sulfoxide (DMSO), or DMSO alone, or were untreated, for the first 5 d of life. The doses chosen were equivalent in biological activity based on published uterine bioassay data (using young adult mice). Observations were made twice daily for 1.5 mo to determine the times of eye and complete vaginal opening. Half of the animals were ovariectomized at 40 d of age. Vaginal lavages were examined for 30 consecutive d beginning both at 2 and at 5 mo of age. DES and coumestrol significantly advanced the time of complete vaginal opening and induced a comparable degree of ovary-independent persistent vaginal cornification. In addition, coumestrol resulted in the occurrence of hemorrhagic ovarian follicles.

Topics: Animals; Body Weight; Castration; Coumarins; Coumestrol; Diethylstilbestrol; Dimethyl Sulfoxide; Female; Injections, Subcutaneous; Mice; Mice, Inbred C57BL; Ovarian Diseases; Ovary; Uterine Diseases; Uterus; Vagina; Vaginal Smears

Coumestrol was examined for its effects upon cholesterol metabolism. Chicks (60) were fed control and coumestrol test diets with added levels of cholesterol for 3 weeks. In the first trial, dietary treatments of 0 ppm coumestrol, 10 ppm coumestrol, 10 ppm coumestrol plus 1% cholesterol, and 1% cholesterol resulted in plasma cholesterol levels of 144, 127, 179, and 193 mg/dl, respectively. Growth rates of chicks were not affected by treatments. The percent ether extract of liver was significantly elevated in chicks fed the diet containing 10 ppm coumestrol and 1% cholesterol. Copper and zinc in liver was reduced in chicks receiving either added dietary coumestrol or cholesterol. A second trial compared diets with 0, .05, .5, 5, and 50 ppm coumestrol. Plasma levels of cholesterol in chicks at 3 wks were 156, 152, 149, 145, and 115 mg/dl, respectively. Liver 3-hydroxy-3-methyl-glutaryl coenzyme A ( HMGCoA ) reductase activity in chicks fed 50 ppm coumestrol was elevated at Day 15 but had returned to control level by Day 21. Maximal HMGCoA reductase activity was found at 2000 hr and least activity at 0400 and 1400 hr. Peak HMGCoA reductase activity appeared strongly influenced by time of feed intake. Apparently, changes in HMGCoA reductase activity are secondary responses to reduced plasma cholesterol due to dietary coumestrol.

Topics: Animals; Body Weight; Chickens; Cholesterol; Cholesterol, Dietary; Circadian Rhythm; Coumarins; Coumestrol; Hydroxymethylglutaryl CoA Reductases; Hydroxymethylglutaryl-CoA-Reductases, NADP-dependent; Microsomes, Liver