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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Estrogen deficiency in the aromatase knockout (ArKO) mouse leads to the development of obesity by as early as 3 months of age, which is characterized by a marked increase in the weights of gonadal and infrarenal fat pads. Humans with natural mutations of the aromatase gene also develop a metabolic syndrome. In the present study cellular and molecular parameters were investigated in gonadal adipose tissue from 10-wk-old wild-type (WT) and ArKO female mice treated with 17beta-estradiol or placebo to identify the basis for the increase in intraabdominal obesity. Stereological examination revealed that adipocytes isolated from ArKO mice were significantly larger and more abundant than adipocytes isolated from WT mice. Upon treatment with estrogen, the volume of these adipocytes was greatly reduced, whereas the reduction in the number of adipocytes was much less pronounced. Transcriptional analysis using real-time PCR revealed concomitant changes with adipocyte volume in the levels of transcripts encoding leptin and lipoprotein lipase, whereas peroxisome proliferator-activated receptor gamma levels followed a pattern closer to that of adipocyte number. Little change was observed in levels of transcripts for factors involved in de novo fatty acid synthesis, beta-oxidation, and lipolysis, suggesting that changes in the uptake of lipids from the circulation are the main mechanisms by which estrogen regulates lipid metabolism in these mice.
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PMID:Cellular and molecular characterization of the adipose phenotype of the aromatase-deficient mouse. 1263 31

The present article summarizes some of the studies available on steroid hormone conversion through the specific expression of steroidogenic enzymes in adipose tissue (adipose tissue intracrinology) and discusses the potential impact of local adipose tissue steroid metabolism on the regulation of adipocyte function and other metabolic parameters. Several studies have demonstrated significant steroid hormone uptake and conversion by adipose tissues from various body sites and in various cell fractions. Activities and/or mRNAs of aromatase, 3beta-hydroxysteroid dehydrogenase (HSD), 3alpha-HSD, 11beta-HSD, 17beta-HSD, 7alpha-hydroxylase, 17alpha-hydroxylase, 5alpha-reductase and UDP-glucuronosyltransferase 2B15 have been detected in adipose tissue or adipose cells. These studies have demonstrated potentially important roles for these enzymes in obesity, central fat accumulation, and the metabolic syndrome. Future studies on adipose tissue intracrinology will contribute further to our understanding of steroid action in adipocytes.
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PMID:Adipose tissue intracrinology: potential importance of local androgen/estrogen metabolism in the regulation of adiposity. 1266 Aug 92

Tamoxifen is a potent antagonist of estrogen, and hepatic steatosis is a frequent complication in adjuvant tamoxifen for breast cancer. Impaired hepatic FA beta-oxidation in peroxisomes, microsomes, and mitochondria results in progression of massive hepatic steatosis in estrogen deficiency. This impairment, although latent, is potentially serious: About 3% of the general population in the United States is now suffering from nonalcoholic steatohepatitis associated with obesity and hyperlipidemia. Therefore, in the present study we tried to restore impaired hepatic FA beta-oxidation by administering a novel statin, pitavastatin, to aromatase-deficient (Ar-/-) mice defective in intrinsic estrogen synthesis. Northern blot analysis of Ar-/- mice liver revealed a significant restoration of mRNA expression of essential enzymes involved in FA beta-oxidation such as very long fatty acyl-CoA synthetase in peroxisome, peroxisomal fatty acyl-CoA oxidase, and medium-chain acyl-CoA dehydrogenase. Severe hepatic steatosis observed in Ar-/- mice substantially regressed. Consistent findings were obtained in the in vitro assays of FA beta-oxidation activity. These findings demonstrate that pitavastatin is capable of restoring impaired FA beta-oxidation in vivo via the peroxisome proliferator-activated receptor-alpha-mediated signaling pathway and is potent enough to ameliorate severe hepatic steatosis in mice deficient in intrinsic estrogen.
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PMID:Pitavastatin ameliorates severe hepatic steatosis in aromatase-deficient (Ar-/-) mice. 1288 Jan 7

The aromatase knockout (ArKO) mouse cannot synthesize endogenous estrogens due to disruption of the Cyp19 gene. We have shown previously, that ArKO mice present with age-progressive obesity and hepatic steatosis, and by 1 yr of age both male and female ArKO mice develop hypercholesterolemia. In this present study 10- to 12-wk-old ArKO mice were challenged for 90 d with high cholesterol diets. Our results show a sexually dimorphic response to estrogen deficiency in terms of cholesterol homeostasis in the liver. ArKO females presented with elevated serum cholesterol; conversely, ArKO males had elevated hepatic cholesterol levels. In response to dietary cholesterol, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase transcript levels were significantly reduced in females, whereas males showed more modest changes. Neither low density lipoprotein nor sterol regulatory element-binding protein expression levels were significantly altered by diet or genotype. The expression of Cyp7a, which encodes cholesterol 7 alpha-hydroxylase, was significantly reduced in ArKO females compared with wild-type females and was increased by cholesterol feeding. Cyp7a expression was significantly elevated in the wild-type males on the high cholesterol diet, although no difference was seen between genotypes on the control diet. The ATP-binding cassette G5 and ATP-binding cassette G8 transporters do not appear to be regulated by estrogen. The expression of acyl-coenzyme A:cholesterol acyltransferase 2 showed a sexually dimorphic response, where estrogen appeared to have a stimulatory effect in females, but not males. This study reveals a sexually dimorphic difference in mouse hepatic cholesterol homeostasis and roles for estrogen in the regulation of cholesterol uptake, biosynthesis, and catabolism in the female, but not in the male.
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PMID:The aromatase knockout mouse presents with a sexually dimorphic disruption to cholesterol homeostasis. 1293 63

Studies from this laboratory have shown that obese men have elevated serum estrogen levels and diminished levels of follicle-stimulating hormone (FSH) and free and total testosterone, all in proportion to their degree of obesity. The decreases in testosterone and FSH constitute a state of hypogonadotropic hypogonadism (HHG), and we have hypothesized that it results from feedback suppression of the pituitary by the elevated estrogen levels. We tested this hypothesis by lowering the serum estrogens of 6 health obese men (body mass index [BMI], 38 to 73) by administering the aromatase inhibitor testolactone (1 g daily for 6 weeks). Twenty-four-hour mean serum testosterone rose in every subject, from a mean of 290 +/- 165 ng/dL to a mean of 403 +/- 170 (P <.0003); 24-hour mean serum estradiol decreased in every subject, from a mean of 40 +/- 10.8 pg/mL to a mean of 29 +/- 6.7 (P <.004); and 24-hour mean serum luteinizing hormone (LH) increased in every subject, from a mean of 14.3 +/- 4.1 mIU/mL to a mean of 19.3 +/- 5.1 (P <.004). The rise in mean LH was due to an increase in the amplitude of the individual secretory pulses, especially at night. Twenty-four-hour mean serum estrone decreased nonsignificantly, from 48 +/- 14 pg/mL to 39 +/- 6.4, and 24-hour mean serum FSH increased nonsignificantly, from 13.5 +/- 5.3 mIU/mL to 15.0 +/- 5.4. The results are in accordance with the hypothesis, in that inhibition of estrogen biosynthesis (through administration of the aromatase inhibitor testolactone) results in alleviation of the HHG of our obese male subjects.
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PMID:Reversal of the hypogonadotropic hypogonadism of obese men by administration of the aromatase inhibitor testolactone. 1450 17

The incidence of newly diagnosed breast cancer cases world-wide is expected to double by 2020. Risk-reducing strategies for breast cancer include lifestyle modifications, chemoprevention and surgery (bilateral mastectomy and/or oophorectomy). Lifestyle modifications include avoidance of postmenopausal obesity and hormone replacement therapy (HRT), regular physical activity, and restriction of alcohol and animal fat intake. Tamoxifen is a selective estrogen receptor modulator (SERM) shown in randomized controlled trials to reduce the incidence of estrogen receptor (ER)-positive breast cancer in high-risk healthy women. However, its routine use cannot be recommended for breast cancer prevention in healthy women due to its significant adverse effects, specifically in terms of endometrial carcinoma and thromboembolism. On the other hand, tamoxifen may be used for chemoprevention in women at high risk of developing ER-positive breast cancer and at low risk of developing complications. Raloxifene, another SERM, also appears to be effective in reducing breast cancer risk, and lacks the unwanted stimulatory effect on the uterus. Other promising chemopreventive agents currently under investigation include cyclo-oxygenase 2 (COX-2) inhibitors, fenretinide, aromatase inhibitors, and goserelin. Prophylactic mastectomy can reduce breast cancer risk by 90% in high-risk women. Bilateral oophorectomy has the potential of reducing the risk of both breast and gynecologic cancer in women carrying BRCA-1 or BRCA-2 mutations. Further research is required to identify novel strategies to prevent ER-negative breast cancer, minimize the adverse effects of tamoxifen and other SERMs, and evaluate the role of mammary ductal lavage and ductoscopy in guiding risk-reducing strategies.
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PMID:Risk-reducing strategies for breast cancer--a review of recent literature. 1564 97

The aromatase (ArKO) knockout mouse develops obesity marked by increased gonadal fat depots. This obesity is characterized by pronounced hypertrophy and hyperplasia in adipocytes with corresponding increases in transcripts involved in fat development. Aromatase deficiency in mice and humans with natural mutations of the aromatase gene also leads to metabolic syndrome, particularly hepatic steatosis. In ArKO mice, this hepatic steatosis, the increased body weight and serum triglycerides are surprisingly prevented by cholesterol feeding. We sought to investigate whether the reduction in body weight upon cholesterol feeding is reflected in gonadal fat depots, which account for a large percentage of body weight in the ArKO mouse. Indeed, gonadal fat depots in female ArKO mice were significantly reduced after cholesterol feeding. Concomitantly, adipocyte hyperplasia and hypertrophy were dramatically reduced upon cholesterol feeding in ArKO mice. Real-time PCR analysis revealed concurrent changes with adipocyte volume in the levels of lipoprotein lipase, caveolin-1 and CD59 transcripts. Little change was observed in levels of transcripts involved in de novo fatty acid synthesis, beta-oxidation, lipolysis, differentiation and cholesterol metabolism, suggesting that cholesterol feeding prevents hyperplasia and hypertrophy of ArKO adipocytes, possibly as a consequence of changes in transcript levels of lipoprotein lipase and therefore fatty acid uptake.
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PMID:Cholesterol feeding prevents adiposity in the obese female aromatase knockout (ArKO) mouse. 1570 35

Scientific attention has been drawn to environmental factors that affect obesity and type II diabetes. Previously, acute organotin toxicosis was reported to induce hyperglycemia without morphological abnormalities in islet tissue, suggesting that these compounds have a direct effect on adipose tissue. Therefore, we investigated the effect of tributyltin (TBT) on adipocyte differentiation. When confluent 3T3-L1 cells were incubated with TBT for 2 days in the presence or absence of isobutyl methylxanthine, dexamethasone and insulin (MDI), the lipid accumulation in adipocytes was greatly enhanced. These morphological changes induced by TBT were accompanied by the expression of a differentiation marker for adipocytes in a dose-dependent manner. Co-treatment with the peroxisome proliferator-activated receptor (PPAR)gamma antagonist GW9662 did not inhibit the effect of TBT, suggesting that the observed effect of TBT may not be PPARgamma-dependent. Although TBT was reported to exert androgenic effects and inhibit the activity of aromatase, treatments with dihydrotestosterone or 17beta-estradiol did not influence the aP2 expression in 3T3-L1 cells, suggesting that the TBT effect does not occur via sex-steroids. These findings indicate that TBT may be one of the environmental chemicals that lead to excessive accumulation of adipose tissue, which can result in obesity.
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PMID:Environmental chemical tributyltin augments adipocyte differentiation. 1599 11

Nutrition is an important regulator of the tempo of human growth. Infancy may represent a critical "window" where variations in nutrition have longer-term consequences for growth and development. Rapid weight gain during infancy is associated with accelerated growth and early pubertal development. Rapid weight gain in infancy is also associated with the development of insulin resistance and an exaggerated adrenarche. Such circulating hormonal changes, together with elevated leptin levels and integral effects of fat cells on hormone action through local 11beta-steroid dehydrogenase and aromatase activity could effect rate of progression of pubertal development in obese subjects. The secular trends in growth and maturation are partly attributed to changing nutrition. Recent data suggest that age at menarche may be static, but there is a debate as to whether the first signs of puberty are being seen much earlier in obese girls. Rapid early weight gain, obesity and early development may have implications for later health through the development of PCOS and overall association with cancer risk.
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PMID:Effects of obesity on growth and puberty. 1615 Mar 81

Polycystic ovary syndrome (PCOS) is a heterogeneous disorder characterized by hirsutism, obesity, hyperandrogenism and insulin resistance. The syndrome is often accompanied by infertility because of anovulation. Many approaches have been proposed to solve this problem, with the most commonly used therapies being ovarian drilling and pharmacological ovulation induction. Ovarian drilling is a procedure in which a laser fiber or electro-surgical needle punctures the ovary four to ten times. Side-effects are rare and often related to surgery itself. Pharmacological strategies include administration of metformin and insulin-sensitizing agents, clomiphene citrate (CC), gonadotropins and aromatase inhibitors. Metformin appears valuable in increasing ovulation rate, menstrual cyclicity and pregnancy rate. CC is an oral estrogen antagonist that raises circulating concentrations of follicle-stimulating hormone (FSH) and induces follicular growth in most women with PCOS and anovulation. Failure to respond is associated with high body mass index and high androgen levels. Aromatase inhibitors mimic the central reduction of negative feedback through which CC works. Ovulation induction with recombinant FSH has proved successful, but treatment requires skill and experience to avoid multiple pregnancies and ovarian hyperstimulation syndrome. The hypothetical deleterious effects of the high luteinizing hormone concentrations observed in PCOS patients seem to be related to the concomitant hyperinsulinemia (and/or insulin resistance). A thorough understanding of the syndrome and a careful assessment of each patient are the mainstays for choosing an appropriate treatment regimen.
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PMID:Therapeutic strategies for ovulation induction in infertile women with polycystic ovary syndrome. 1639 Jul 83


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