Fetal Programming of Adult Glucose Homeostasis in Mice

BACKGROUND: Emerging evidence suggests that dietary soy and phytoestrogens can have beneficial effects on lipid and glucose metabolism. We have previously shown that male mice fed from conception to adulthood with a high soy-containing diet had reduced body weight, adiposity and a decrease in glucose intolerance, an early marker of insulin resistance and diabetes. OBJECTIVES: The purpose of this study was to identify the precise periods of exposure during which phytoestrogens and dietary soy improve lipid and glucose metabolism. Since intrauterine position (IUP) has been shown to alter sensitivity to endocrine disruptors, we also investigated whether the combination of IUP and fetal exposure to dietary phytoestrogens could potentially affect adult metabolic parameters. METHODS: Male outbred mice (CD-1) were allowed ad libitum access to either a high soy-containing diet or a soy-free diet either during gestation, lactation or after weaning. Adiposity and bone mass density was assessed by dual x-ray absorptiometry. Glucose tolerance was assessed by a glucose tolerance test. Blood pressure was examined by the tail-cuff system. RESULTS: Here we show that metabolic improvements are dependent on precise windows of exposure during life. The beneficial effects of dietary soy and phytoestrogens on adiposity were apparent only in animals fed post-natally, while the improvements in glucose tolerance are restricted to animals with fetal exposure to soy. Interestingly, we observed that IUP influenced adult glucose tolerance, but not adiposity. Similar IUP trends were observed for other estrogen-related metabolic parameters such as blood pressure and bone mass density. CONCLUSION: Our results suggest that IUP and fetal exposure to estrogenic environmental disrupting compounds, such as dietary phytoestrogens, could alter metabolic and cardiovascular parameters in adult individuals independently of adipose gain

The Molecular Chaperone Hsp90α Is Required for Meiotic Progression of Spermatocytes beyond Pachytene in the Mouse

The molecular chaperone Hsp90 has been found to be essential for viability in all tested eukaryotes, from the budding yeast to Drosophila. In mammals, two genes encode the two highly similar and functionally largely redundant isoforms Hsp90α and Hsp90β. Although they are co-expressed in most if not all cells, their relative levels vary between tissues and during development. Since mouse embryos lacking Hsp90β die at implantation, and despite the fact that Hsp90 inhibitors being tested as anti-cancer agents are relatively well tolerated, the organismic functions of Hsp90 in mammals remain largely unknown. We have generated mouse lines carrying gene trap insertions in the Hsp90α gene to investigate the global functions of this isoform. Surprisingly, mice without Hsp90α are apparently normal, with one major exception. Mutant male mice, whose Hsp90β levels are unchanged, are sterile because of a complete failure to produce sperm. While the development of the male reproductive system appears to be normal, spermatogenesis arrests specifically at the pachytene stage of meiosis I. Over time, the number of spermatocytes and the levels of the meiotic regulators and Hsp90 interactors Hsp70-2, NASP and Cdc2 are reduced. We speculate that Hsp90α may be required to maintain and to activate these regulators and/or to disassemble the synaptonemal complex that holds homologous chromosomes together. The link between fertility and Hsp90 is further supported by our finding that an Hsp90 inhibitor that can cross the blood-testis barrier can partially phenocopy the genetic defects

Short-Term Treatment with Bisphenol-A Leads to Metabolic Abnormalities in Adult Male Mice

Bisphenol-A (BPA) is one of the most widespread endocrine disrupting chemicals (EDC) used as the base compound in the manufacture of polycarbonate plastics. Although evidence points to consider exposure to BPA as a risk factor for insulin resistance, its actions on whole body metabolism and on insulin-sensitive tissues are still unclear. The aim of the present work was to study the effects of low doses of BPA in insulin-sensitive peripheral tissues and whole body metabolism in adult mice. Adult mice were treated with subcutaneous injection of 100 µg/kg BPA or vehicle for 8 days. Whole body energy homeostasis was assessed with in vivo indirect calorimetry. Insulin signaling assays were conducted by western blot analysis. Mice treated with BPA were insulin resistant and had increased glucose-stimulated insulin release. BPA-treated mice had decreased food intake, lower body temperature and locomotor activity compared to control. In skeletal muscle, insulin-stimulated tyrosine phosphorylation of the insulin receptor β subunit was impaired in BPA-treated mice. This impairment was associated with a reduced insulin-stimulated Akt phosphorylation in the Thr308 residue. Both skeletal muscle and liver displayed an upregulation of IRS-1 protein by BPA. The mitogen-activated protein kinase (MAPK) signaling pathway was also impaired in the skeletal muscle from BPA-treated mice. In the liver, BPA effects were of lesser intensity with decreased insulin-stimulated tyrosine phosphorylation of the insulin receptor β subunit

Does Glycine max leaves or Garcinia Cambogia promote weight-loss or lower plasma cholesterol in overweight individuals: a randomized control trial

<p>Abstract</p> <p>Background</p> <p>Natural food supplements with high flavonoid content are often claimed to promote weight-loss and lower plasma cholesterol in animal studies, but human studies have been more equivocal. The aim of this study was firstly to determine the effectiveness of natural food supplements containing <it>Glycine max </it>leaves extract (EGML) or <it>Garcinia cambogia </it>extract (GCE) to promote weight-loss and lower plasma cholesterol. Secondly to examine whether these supplements have any beneficial effect on lipid, adipocytokine or antioxidant profiles.</p> <p>Methods</p> <p>Eighty-six overweight subjects (Male:Female = 46:40, age: 20~50 yr, BMI > 23 < 29) were randomly assigned to three groups and administered tablets containing EGML (2 g/day), GCE (2 g/day) or placebo (starch, 2 g/day) for 10 weeks. At baseline and after 10 weeks, body composition, plasma cholesterol and diet were assessed. Blood analysis was also conducted to examine plasma lipoproteins, triglycerides, adipocytokines and antioxidants.</p> <p>Results</p> <p>EGML and GCE supplementation failed to promote weight-loss or any clinically significant change in %body fat. The EGML group had lower total cholesterol after 10 weeks compared to the placebo group (p < 0.05). EGML and GCE had no effect on triglycerides, non-HDL-C, adipocytokines or antioxidants when compared to placebo supplementation. However, HDL-C was higher in the EGML group (p < 0.001) after 10 weeks compared to the placebo group.</p> <p>Conclusions</p> <p>Ten weeks of EGML or GCE supplementation did not promote weight-loss or lower total cholesterol in overweight individuals consuming their habitual diet. Although, EGML did increase plasma HDL-C levels which is associated with a lower risk of atherosclerosis.</p

Dicer1 Depletion in Male Germ Cells Leads to Infertility Due to Cumulative Meiotic and Spermiogenic Defects

Background: Spermatogenesis is a complex biological process that requires a highly specialized control of gene expression. In the past decade, small non-coding RNAs have emerged as critical regulators of gene expression both at the transcriptional and post-transcriptional level. DICER1, an RNAse III endonuclease, is essential for the biogenesis of several classes of small RNAs, including microRNAs (miRNAs) and endogenous small interfering RNAs (endo-siRNAs), but is also critical for the degradation of toxic transposable elements. In this study, we investigated to which extent DICER1 is required for germ cell development and the progress of spermatogenesis in mice.Principal Findings: We show that the selective ablation of Dicer1 at the early onset of male germ cell development leads to infertility, due to multiple cumulative defects at the meiotic and post-meiotic stages culminating with the absence of functional spermatozoa. Alterations were observed in the first spermatogenic wave and include delayed progression of spermatocytes to prophase I and increased apoptosis, resulting in a reduced number of round spermatids. The transition from round to mature spermatozoa was also severely affected, since the few spermatozoa formed in mutant animals were immobile and misshapen, exhibiting morphological defects of the head and flagellum. We also found evidence that the expression of transposable elements of the SINE family is up-regulated in Dicer1-depleted spermatocytes.Conclusions/Significance: Our findings indicate that DICER1 is dispensable for spermatogonial stem cell renewal and mitotic proliferation, but is required for germ cell differentiation through the meiotic and haploid phases of spermatogenesis

Effect of Carnitine and herbal mixture extract on obesity induced by high fat diet in rats

<p>Abstract</p> <p>Background</p> <p>Obesity-associated type 2 diabetes is rapidly increasing throughout the world. It is generally recognized that natural products with a long history of safety can modulate obesity.</p> <p>Aim</p> <p>To investigate the development of obesity in response to a high fat diet (HFD) and to estimate the effect of L-carnitine and an Egyptian Herbal mixture formulation (HMF) (consisting of T. chebula, Senae, rhubarb, black cumin, aniseed, fennel and licorice) on bodyweight, food intake, lipid profiles, renal, hepatic, cardiac function markers, lipid Peroxidation, and the glucose and insulin levels in blood and liver tissue in rats.</p> <p>Method</p> <p>White male albino rats weighing 80-90 gm, 60 days old. 10 rats were fed a normal basal diet (Cr), 30 rats fed a high-fat diet (HFD) for 14 weeks during the entire study. Rats of the HFD group were equally divided into 3 subgroups each one include 10 rats. The first group received HFD with no supplement (HFD), the 2^ndgroup HFD+L-carnitine and the third group received HFD+HMF. Carnitine and HMF were administered at 10^thweek (start time for treatments) for 4 weeks.</p> <p>Body weight, lipid profile & renal function (urea, uric acid creatinine) ALT & AST activities, cardiac markers, (LDH, C.K-NAC and MB) the oxidative stress marker reduced glutathione (GSH), and Malondialdehyde (MDA) catalase activity, in addition to glucose, insulin, and insulin resistance in serum & tissues were analyzed.</p> <p>Results</p> <p>Data showed that feeding HFD diet significantly increased final body weight, triglycerides (TG), total cholesterol, & LDL concentration compared with controls, while significantly decreasing HDL; meanwhile treatment with L-carnitine, or HMF significantly normalized the lipid profile.</p> <p>Serum ALT, urea, uric acid, creatinine, LDH, CK-NAC, CK-MB were significantly higher in the high fat group compared with normal controls; and administration of L-carnitine or herbal extract significantly lessened the effect of the HFD. Hyperglycemia, hyperinsulinemia, and high insulin resistance (IR) significantly increased in HFD in comparison with the control group. The treatment with L-carnitine or HMF improved the condition. HFD elevated hepatic MDA and lipid peroxidation associated with reduction in hepatic GSH and catalase activity; whereas administration of L-carnitine or herbal extract significantly ameliorated these hepatic alterations.</p> <p>Conclusion</p> <p>HFD induced obesity associated with a disturbed lipid profile, defective antioxidant stability, and high values of IR parameters; this may have implications for the progress of obesity related problems. Treatment with L-carnitine, or HMF extract improved obesity and its associated metabolic problems in different degrees. Also HMF has antioxidant, hypolipidaemic insulin sensitizing effects. Moreover HMF might be a safe combination on the organs whose functions were examined, as a way to surmount the obesity state; and it has a distinct anti-obesity effect.</p

Global age-sex-specific fertility, mortality, healthy life expectancy (HALE), and population estimates in 204 countries and territories, 1950-2019: a comprehensive demographic analysis for the Global Burden of Disease Study 2019.

BACKGROUND: Accurate and up-to-date assessment of demographic metrics is crucial for understanding a wide range of social, economic, and public health issues that affect populations worldwide. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 produced updated and comprehensive demographic assessments of the key indicators of fertility, mortality, migration, and population for 204 countries and territories and selected subnational locations from 1950 to 2019. METHODS: 8078 country-years of vital registration and sample registration data, 938 surveys, 349 censuses, and 238 other sources were identified and used to estimate age-specific fertility. Spatiotemporal Gaussian process regression (ST-GPR) was used to generate age-specific fertility rates for 5-year age groups between ages 15 and 49 years. With extensions to age groups 10-14 and 50-54 years, the total fertility rate (TFR) was then aggregated using the estimated age-specific fertility between ages 10 and 54 years. 7417 sources were used for under-5 mortality estimation and 7355 for adult mortality. ST-GPR was used to synthesise data sources after correction for known biases. Adult mortality was measured as the probability of death between ages 15 and 60 years based on vital registration, sample registration, and sibling histories, and was also estimated using ST-GPR. HIV-free life tables were then estimated using estimates of under-5 and adult mortality rates using a relational model life table system created for GBD, which closely tracks observed age-specific mortality rates from complete vital registration when available. Independent estimates of HIV-specific mortality generated by an epidemiological analysis of HIV prevalence surveys and antenatal clinic serosurveillance and other sources were incorporated into the estimates in countries with large epidemics. Annual and single-year age estimates of net migration and population for each country and territory were generated using a Bayesian hierarchical cohort component model that analysed estimated age-specific fertility and mortality rates along with 1250 censuses and 747 population registry years. We classified location-years into seven categories on the basis of the natural rate of increase in population (calculated by subtracting the crude death rate from the crude birth rate) and the net migration rate. We computed healthy life expectancy (HALE) using years lived with disability (YLDs) per capita, life tables, and standard demographic methods. Uncertainty was propagated throughout the demographic estimation process, including fertility, mortality, and population, with 1000 draw-level estimates produced for each metric. FINDINGS: The global TFR decreased from 2·72 (95% uncertainty interval [UI] 2·66-2·79) in 2000 to 2·31 (2·17-2·46) in 2019. Global annual livebirths increased from 134·5 million (131·5-137·8) in 2000 to a peak of 139·6 million (133·0-146·9) in 2016. Global livebirths then declined to 135·3 million (127·2-144·1) in 2019. Of the 204 countries and territories included in this study, in 2019, 102 had a TFR lower than 2·1, which is considered a good approximation of replacement-level fertility. All countries in sub-Saharan Africa had TFRs above replacement level in 2019 and accounted for 27·1% (95% UI 26·4-27·8) of global livebirths. Global life expectancy at birth increased from 67·2 years (95% UI 66·8-67·6) in 2000 to 73·5 years (72·8-74·3) in 2019. The total number of deaths increased from 50·7 million (49·5-51·9) in 2000 to 56·5 million (53·7-59·2) in 2019. Under-5 deaths declined from 9·6 million (9·1-10·3) in 2000 to 5·0 million (4·3-6·0) in 2019. Global population increased by 25·7%, from 6·2 billion (6·0-6·3) in 2000 to 7·7 billion (7·5-8·0) in 2019. In 2019, 34 countries had negative natural rates of increase; in 17 of these, the population declined because immigration was not sufficient to counteract the negative rate of decline. Globally, HALE increased from 58·6 years (56·1-60·8) in 2000 to 63·5 years (60·8-66·1) in 2019. HALE increased in 202 of 204 countries and territories between 2000 and 2019. INTERPRETATION: Over the past 20 years, fertility rates have been dropping steadily and life expectancy has been increasing, with few exceptions. Much of this change follows historical patterns linking social and economic determinants, such as those captured by the GBD Socio-demographic Index, with demographic outcomes. More recently, several countries have experienced a combination of low fertility and stagnating improvement in mortality rates, pushing more populations into the late stages of the demographic transition. Tracking demographic change and the emergence of new patterns will be essential for global health monitoring. FUNDING: Bill & Melinda Gates Foundation

Diethylstilboestrol exposure does not reduce testosterone production in human fetal testis xenografts

In rodents, in utero exposure to exogenous estrogens including diethylstilboestrol (DES) results in major suppression of steroidogenesis in fetal testes. Whether similar effects occur in the human fetal testis is equivocal. Based on the results of the rodent studies, we hypothesised that exposure of human fetal testes to DES would result in a reduction in testosterone production. We show, using a xenograft approach, that testosterone production is not reduced in human fetal testis following DES exposure. Human fetal testes (15-19 weeks' gestation, n = 6) were xenografted into castrate male nude mice which were then treated for 35 days with vehicle or 100 µg/kg DES three times a week. For comparison, similar treatment was applied to pregnant rats from e13.5-e20.5 and effects on fetal testes evaluated at e21.5. Xenograft testosterone production was assessed by measuring host seminal vesicle (SV) weights as an indirect measure over the entire grafting period, and single measurement of serum testosterone at termination. Human fetal testis xenografts showed similar survival in DES and vehicle-exposed hosts. SV weight (44.3 v 26.6 mg, p = 0.01) was significantly increased in DES compared to vehicle-exposed hosts, respectively, indicating an overall increase in xenograft testosterone production over the grafting period, whilst serum testosterone at termination was unchanged. In contrast intra-testicular testosterone levels were reduced by 89%, in fetal rats exposed to DES. In rats, DES effects are mediated via Estrogen Receptor α (ESR1). We determined ESR1 protein and mRNA expression in human and rat fetal testis. ESR1 was expressed in rat, but not in human, fetal Leydig cells. We conclude that human fetal testis exposure to DES does not impair testosterone production as it does in rats, probably because ESR1 is not expressed in human fetal Leydig cells. This indicates that DES exposure is likely to pose minimal risk to masculinization of the human fetus