scholarly journals Organophosphate Flame-Retardants Alter Adult Mouse Homeostasis and Gene Expression in a Sex-Dependent Manner Potentially Through Interactions With ERα

2017 ◽  
Vol 162 (1) ◽  
pp. 212-224 ◽  
Author(s):  
Elizabeth A Krumm ◽  
Vipa J Patel ◽  
Taylor S Tillery ◽  
Ali Yasrebi ◽  
Jianliang Shen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Body Weight ◽  
Polybrominated Diphenyl Ethers ◽  
Flame Retardants ◽  
Dependent Manner ◽  
Hormone Levels ◽  
Glucose Levels ◽  
Insulin Tolerance ◽  
Plasma Hormone ◽  
Liver Gene

Abstract Flame retardants (FRs) such as polybrominated diphenyl ethers and organophosphate FR (OPFR) persist in the environment and interact with multiple nuclear receptors involved in homeostasis, including estrogen receptors (ERs). However, little is known about the effects of FR, especially OPFR, on mammalian neuroendocrine functions. Therefore, we investigated if exposure to FR alters hypothalamic gene expression and whole-animal physiology in adult wild-type (WT) and ERα KO mice. Intact WT and KO males and ovariectomized WT and KO females were orally dosed daily with vehicle (oil), 17α-ethynylestradiol (2.5 μg/kg), 2,2’, 4,4-tetrabromodiphenyl ether (BDE-47, 1 or 10 mg/kg), or an OPFR mixture {1 or 10 mg/kg of tris(1, 3-dichloro-2-propyl)phosphate, triphenyl phosphate, and tricresyl phosphate each} for 28 days. Body weight, food intake, body composition, glucose and insulin tolerance, plasma hormone levels, and hypothalamic and liver gene expression were measured. Expression of neuropeptides, receptors, and cation channels was differentially altered between WT males and females. OPFR suppressed body weight and energy intake in males. FR increased fasting glucose levels in males, and BDE-47 augmented glucose clearance in females. Liver gene expression indicated FXR activation by BDE-47 and PXR and CAR activation by OPFR. In males, OPFR increased ghrelin but decreased leptin and insulin independent of body weight. The loss of ERα reduced the effects of both FR on hypothalamic and liver gene expression and plasma hormone levels. The physiological implications are that males are more sensitive than ovariectomized females to OPFR exposure and that these effects are mediated, in part, by ERα.

Effect of a Polyphenol-Rich Extract from Aloe vera Gel on Experimentally Induced Insulin Resistance in Mice

2007 ◽  
Vol 35 (06) ◽  
pp. 1037-1046 ◽  
Author(s):  
Yolanda Y. Pérez ◽  
Enrique Jiménez-Ferrer ◽  
Alejandro Zamilpa ◽  
Marcelino Hernández-Valencia ◽  
Francisco J. Alarcón-Aguilar ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Body Weight ◽  
Aloe Vera ◽  
Negative Control Group ◽  
Negative Control ◽  
Control Group ◽  
Glucose Levels ◽  
Insulin Tolerance ◽  
Aloe Vera Gel ◽  
Experimentally Induced

Insulin resistance, which precedes type 2 diabetes mellitus (T2DM), is a widespread pathology associated with the metabolic syndrome, myocardial ischemia, and hypertension. Finding an adequate treatment for this pathology is an important goal in medicine. The purpose of the present research was to investigate the effect of an extract from Aloe vera gel containing a high concentration of polyphenols on experimentally induced insulin resistance in mice. A polyphenol-rich Aloe vera extract (350 mg/kg) with known concentrations of aloin (181.7 mg/g) and aloe-emodin (3.6 mg/g) was administered orally for a period of 4 weeks to insulin resistant ICR mice. Pioglitazone (50 mg/kg) and bi-distilled water were used as positive and negative controls respectively. Body weight, food intake, and plasma concentrations of insulin and glucose were measured and insulin tolerance tests were performed. The insulin resistance value was calculated using the homeostasis model assessment for insulin resistance (HOMA-IR) formula. Results showed that the polyphenol-rich extract from Aloe vera was able to decrease significantly both body weight ( p < 0.008) and blood glucose levels ( p < 0.005) and to protect animals against unfavorable results on HOMA-IR, which was observed in the negative control group. The highest glucose levels during the insulin tolerance curve test were in the negative control group when compared to the Aloe vera extract and pioglitazone treated mice ( p < 0.05). In conclusion, Aloe vera gel could be effective for the control of insulin resistance.

scholarly journals Sex-Dependent Liver Gene Expression Is Extensive and Largely Dependent upon Signal Transducer and Activator of Transcription 5b (STAT5b): STAT5b-Dependent Activation of Male Genes and Repression of Female Genes Revealed by Microarray Analysis

2006 ◽  
Vol 20 (6) ◽  
pp. 1333-1351 ◽  
Author(s):  
Karl H. Clodfelter ◽  
Minita G. Holloway ◽  
Paul Hodor ◽  
Soo-Hee Park ◽  
William J. Ray ◽  
...  
Keyword(s):  
Gene Expression ◽  
Sex Differences ◽  
Large Scale ◽  
Dependent Manner ◽  
Signal Transducer ◽  
Genotype Combination ◽  
Hepatic Expression ◽  
Gh Secretion ◽  
Liver Gene ◽  
Plasma Gh

Abstract Sexual dimorphism in mammalian liver contributes to sex differences in physiology, homeostasis, and steroid and foreign compound metabolism. Many sex-dependent liver genes are regulated by sex differences in pituitary GH secretion, with the transcription factor, signal transducer and activator of transcription (STAT5b), proposed to mediate signaling by the pulsatile, male plasma GH profile. Presently, a large-scale gene expression study was conducted using male and female mice, wild type and Stat5b inactivated, to characterize sex differences in liver gene expression and their dependence on STAT5b. The relative abundance of individual liver RNAs was determined for each sex-genotype combination by competitive hybridization to 23,574-feature oligonucleotide microarrays. Significant sex differences in hepatic expression were seen for 1603 mouse genes. Of 850 genes showing higher expression in males, 767 (90%) were down-regulated in STAT5b-deficient males. Moreover, of 753 genes showing female-predominant expression, 461 (61%) were up-regulated in STAT5b-deficient males. In contrast, approximately 90% of the sex-dependent genes were unaffected by STAT5b deficiency in females. Thus: 1) STAT5b is essential for sex-dependent liver gene expression, a characteristic of approximately 1600 mouse genes (4% of the genome); 2) male-predominant liver gene expression requires STAT5b, or STAT5b-dependent factors, which act in a positive manner; and 3) many female-predominant liver genes are repressed in males in a STAT5b-dependent manner. Several of the STAT5b-dependent male genes encode transcriptional repressors; these may include direct STAT5b targets that repress female-predominant genes in male liver. Several female-predominant repressors are elevated in STAT5b-deficient males; these may contribute to the major loss of male gene expression seen in the absence of STAT5b.

scholarly journals Elaiophylin reduces body weight and lowers glucose levels in obese mice by activating AMPK

2021 ◽  
Vol 12 (11) ◽  
Author(s):  
Ruoxuan Bao ◽  
Yongmei Meng ◽  
Haibo Zhang ◽  
Chen Yang ◽  
Wei Li ◽  
...  
Keyword(s):  
Body Weight ◽  
Chronic Diseases ◽  
Therapeutic Potential ◽  
In Vivo Studies ◽  
Pharmacological Intervention ◽  
Obese Mouse ◽  
Acid Oxidation ◽  
Dependent Manner ◽  
Glucose Levels ◽  
Treatment Of Obesity

AbstractObesity is an epidemic affecting 13% of the global population and increasing the risk of many chronic diseases. However, only several drugs are licensed for pharmacological intervention for the treatment of obesity. As a master regulator of metabolism, the therapeutic potential of AMPK is widely recognized and aggressively pursued for the treatment of metabolic diseases. We found that elaiophylin (Ela) rapidly activates AMPK in a panel of cancer-cell lines, as well as primary hepatocytes and adipocytes. Meanwhile, Ela inhibits the mTORC1 complex, turning on catabolism and turning off anabolism together with AMPK. In vitro and in vivo studies showed that Ela does not activate AMPK directly, instead, it increases cellular AMP/ATP and ADP/ATP ratios, leading to AMPK phosphorylation in a LKB1-dependent manner. AMPK activation induced by Ela caused changes in diverse metabolic genes, thereby promoting glucose consumption and fatty acid oxidation. Importantly, Ela activates AMPK in mouse liver and adipose tissue. As a consequence, it reduces body weight and blood glucose levels and improves glucose and insulin tolerance in both ob/ob and high-fat diet-induced obese mouse models. Our study has identified a novel AMPK activator as a candidate drug for the treatment of obesity and its associated chronic diseases.

scholarly journals Effects of Magnesium Biotinate Supplementation on Serum Insulin, Glucose, and Lipid Parameters Along with Gene Expressions of Intermediary Metabolism in Rats

2020 ◽  
Author(s):  
Kazim Sahin ◽  
Cemal ORHAN ◽  
Osman KUCUK ◽  
Mehmet TUZCU ◽  
Nurhan SAHIN ◽  
...  
Keyword(s):  
Gene Expression ◽  
Body Weight ◽  
Serum Insulin ◽  
Intermediary Metabolism ◽  
Standard Diet ◽  
Serum Concentrations ◽  
Sprague Dawley ◽  
Gene Expressions ◽  
Liver Gene ◽  
Biotin Supplementation

Abstract Background: The objective of this work was to investigate the effects of a novel form of biotin (magnesium biotinate) at various levels on body weight, serum concentrations of glucose, insulin, cholesterol, and triglycerides, and liver expression of lipid metabolism-related genes such as SREBP-1c, FAS, AMPK-α1, ACC-1, ACC-2, PC, PCC and MCC in rats.Methods: A total of 42 male Sprague-Dawley rats were divided into six treatment groups and fed a standard diet-based egg white powdered diet supplemented with either commercial biotin (d-biotin) at 0.01, 1 or 100 mg/kg body weight or a novel form of biotin (magnesium biotinate) at 0.01, 1, or 100 mg/kg bodyweight for 35 days. The doses used at 0.01, 1 and 100 mg from each source represented a standard dietary dose (control), high dietary dose, and pharmacologic dose, respectively. Results: Bodyweight changes, feed intake, serum concentrations of glucose, insulin, creatine, and urea, and enzyme activities of ALT and AST were similar among treatments (P > 0.05). Serum total cholesterol and triglyceride concentrations of the rats decreased with biotin supplementation from both sources (P < 0.05). Concentrations were significantly lower with magnesium biotinate when comparing the 1 mg/kg dose groups (P < 0.05). Serum, liver, brain biotin concentrations, and liver cGMP contents were greater when rats were treated with magnesium biotinate versus d-biotin, particularly when comparing the 1 mg/kg and 100 mg/kg dose groups (P < 0.05). Both forms of biotin decreased the liver gene expression of SREBP‐1c and FAS and increased liver gene expression of AMPK-α1, ACC-1, ACC-2, PCC and MCC (P < 0.05). The magnitudes of responses were more emphasized with magnesium biotinate. Liver PC gene expression increased with biotin supplementation with no regard to dose or biotin form (P > 0.05).Conclusion: Results of the present work revealed that a new form of biotin, magnesium biotinate, compared with a commercial d-biotin, is more effective in reducing serum lipid concentrations and in regulating gene expressions of intermediary metabolism-related biomarkers.

scholarly journals In Utero and Lactational Exposure to Flame Retardants Disrupts Rat Ovarian Follicular Development and Advances Puberty

2020 ◽  
Vol 175 (2) ◽  
pp. 197-209 ◽  
Author(s):  
Adélaïde Allais ◽  
Océane Albert ◽  
Pavine L C Lefèvre ◽  
Michael G Wade ◽  
Barbara F Hales ◽  
...  
Keyword(s):  
Gene Expression ◽  
Polybrominated Diphenyl Ethers ◽  
Flame Retardants ◽  
Ovarian Function ◽  
Expression Patterns ◽  
Follicular Development ◽  
In Utero ◽  
Consumer Products ◽  
Sprague Dawley ◽  
Lactational Exposure

Abstract Brominated flame retardants (BFRs), including polybrominated diphenyl ethers and hexabromocyclododecane, leach out from consumer products into the environment. Exposure to BFRs has been associated with effects on endocrine homeostasis. To test the hypothesis that in utero and lactational exposure to BFRs may affect the reproductive system of female offspring, adult female Sprague Dawley rats were fed diets formulated to deliver nominal doses (0, 0.06, 20, or 60 mg/kg/day) of a BFR dietary mixture mimicking the relative congener levels in house dust from prior to mating until weaning. Vaginal opening and the day of first estrus occurred at a significantly earlier age among offspring from the 20 mg/kg/day BFR group, indicating that the onset of puberty was advanced. Histological analysis of ovaries from postnatal day 46 offspring revealed an increase in the incidence of abnormal follicles. A toxicogenomic analysis of ovarian gene expression identified upstream regulators, including HIF1A, CREB1, EGF, the β-estradiol, and PPARA pathways, predicted to be downregulated in the 20 or 60 mg/kg/day group and to contribute to the gene expression patterns observed. Thus, perinatal exposure to BFRs dysregulated ovarian folliculogenesis and signaling pathways that are fundamental for ovarian function in the adult.

scholarly journals Central and Peripheral Mechanisms in ApoE4-Driven Diabetic Pathology

2020 ◽  
Vol 21 (4) ◽  
pp. 1289
Author(s):  
Amit Koren-Iton ◽  
Shiran Salomon-Zimri ◽  
Alex Smolar ◽  
Efrat Shavit-Stein ◽  
Amir Dori ◽  
...  
Keyword(s):  
Glycogen Synthase ◽  
Control Diet ◽  
Fasting Blood Glucose ◽  
Apoe Genotype ◽  
Dependent Manner ◽  
Fiber Density ◽  
Akt Activation ◽  
Glucose Levels ◽  
Insulin Tolerance ◽  
Gsk 3Β

Apolipoprotein E (APOE) ε4 gene allele and type 2 diabetes mellitus (T2DM) are prime risk factors for Alzheimer’s disease (AD). Despite evidence linking T2DM and apoE4, the mechanism underlying their interaction is yet to be determined. In the present study, we employed a model of APOE-targeted replacement mice and high-fat diet (HFD)-induced insulin resistance to investigate diabetic mechanisms associated with apoE4 pathology and the extent to which they are driven by peripheral and central processes. Results obtained revealed an intriguing pattern, in which under basal conditions, apoE4 mice display impaired glucose and insulin tolerance and decreased insulin secretion, as well as cognitive and sensorimotor characteristics relative to apoE3 mice, while the HFD impairs apoE3 mice without significantly affecting apoE4 mice. Measurements of weight and fasting blood glucose levels increased in a time-dependent manner following the HFD, though no effect of genotype was observed. Interestingly, sciatic electrophysiological and skin intra-epidermal nerve fiber density (IENFD) peripheral measurements were not affected by the APOE genotype or HFD, suggesting that the observed sensorimotor and cognitive phenotypes are related to central nervous system processes. Indeed, measurements of hippocampal insulin receptor and glycogen synthase kinase-3β (GSK-3β) activation revealed a pattern similar to that obtained in the behavioral measurements while Akt activation presented a dominant effect of diet. HFD manipulation induced genotype-independent hyperlipidation of apoE, and reduced levels of brain apoE in apoE3 mice, rendering them similar to apoE4 mice, whose brain apoE levels were not affected by the diet. No such effect was observed in the peripheral plasma levels of apoE, suggesting that the pathological effects of apoE4 under the control diet and apoE3 under HFD conditions are related to the decreased levels of brain apoE. Taken together, our data suggests that diabetic mechanisms play an important role in mediating the pathological effects of apoE4 and that consequently, diabetic-related therapy may be useful in treating apoE4 pathology in AD.

scholarly journals EFFECT OF CALORIC RESTRICTION AND RAPAMYCIN ON OVARIAN AGING IN MICE

2019 ◽  
Vol 3 (Supplement_1) ◽  
pp. S103-S103
Author(s):  
Driele Garcia ◽  
Tatiana Saccon ◽  
Joao Rincon ◽  
Jorgea Pradiee ◽  
Rafael Mondadori ◽  
...  
Keyword(s):  
Gene Expression ◽  
Body Weight ◽  
Caloric Restriction ◽  
Primordial Follicle ◽  
Tolerance Test ◽  
Metabolic Effects ◽  
Primordial Follicles ◽  
Female Mice ◽  
Insulin Tolerance ◽  
Follicular Reserve

Abstract The ovarian follicular reserve of primordial follicle declines with aging in female mammals. Caloric restriction (CR) has been shown to increase the preservation of the ovarian follicular reserve. Likewise, rapamycin has similar effects to CR on the ovarian reserve. Therefore, the aim of our study was to evaluate the effects of rapamycin and CR on the metabolism and ovarian follicular reserve and gene expression in mice. Thirty-six female mice were used, and allocated into 3 groups: control, rapamycin (4mg/kg body weight every other day) and 30% CR. At 85 days of treatment, an insulin tolerance test (ITT) and glucose tolerance test (GTT) was performed. At 93 days ovaries were collected for analysis. CR females had lower body weight (P&lt;0.05) and were more insulin sensitive (P=0.003), while rapamycin treated females did not change body weight (P&gt;0.05) and were more resistant to insulin (P&lt;0.05). Females from the CR and rapamycin groups had a twice higher number of primordial follicles (P=0.02 and 0.04) and half the number of primary, secondary and tertiary follicles (P&lt;0.05). Both CR and rapamycin females had increased ovarian gene expression of Foxo3a mRNA (P&lt;0.05). In conclusion, female mice from rapamycin and CR groups had an increased ovarian follicular reserve associated to higher expression of Foxo3a mRNA, despite divergent metabolic effects of the treatments.

scholarly journals Anorectic Effects of the Cytokine, Ciliary Neurotropic Factor, Are Mediated by Hypothalamic Neuropeptide Y: Comparison with Leptin*

Endocrinology ◽  
1998 ◽  
Vol 139 (2) ◽  
pp. 466-473 ◽  
Author(s):  
B. Xu ◽  
M. G. Dube ◽  
P. S. Kalra ◽  
W. G. Farmerie ◽  
A. Kaibara ◽  
...  
Keyword(s):  
Gene Expression ◽  
Weight Loss ◽  
Body Weight ◽  
Food Intake ◽  
Neuropeptide Y ◽  
Messenger Rna ◽  
Nervous System Development ◽  
Ribonuclease Protection Assay ◽  
Dependent Manner ◽  
Neurotropic Factor

Abstract Although ciliary neurotropic factor (CNTF) is a tropic factor in nervous system development and maintenance, peripheral administration of this cytokine also causes severe anorexia and weight loss. The neural mechanism(s) mediating the loss of appetite is not known. As hypothalamic neuropeptide Y (NPY) is a potent orexigenic signal, we tested the hypothesis that CNTF may adversely affect NPYergic signaling in the hypothalamus. Intraperitoneal administration of CNTF (250μ g/kg) daily for 4 days significantly suppressed 24-h food intake in a time-dependent manner and decreased body weight. The loss in body weight was similar to that which occurred in pair-fed (PF) rats. As expected, hypothalamic NPY gene expression, determined by measurement of steady state prepro-NPY messenger RNA by ribonuclease protection assay, significantly increased in PF rats in response to energy imbalance. However, despite a similar loss in body weight, there was no increase in NPY gene expression in CNTF-treated rats. Daily administration of CNTF intracerebroventricularly (0.5 or 5.0 μg/rat) also produced anorexia and body weight loss. In this experiment, negative energy balance produced by both PF and food deprivation augmented hypothalamic NPY gene expression. However, despite reduced intake and loss of body weight, no similar increment in hypothalamic NPY gene expression was observed in CNTF-treated rats. In fact, in rats treated with higher doses of CNTF (5.0 μg/rat), NPY gene expression was reduced below the levels seen in control, freely fed rats. Furthermore, CNTF treatment also markedly decreased NPY-induced feeding. These results suggested that anorexia in CNTF-treated rats may be due to a deficit in NPY supply and possibly in the release and suppression of NPY-induced feeding. The possibility that CNTF-induced anorexia may be caused by increased leptin was next examined. Daily intracerebroventricular injections of leptin (7 μg/rat) decreased food intake, body weight, and hypothalamic NPY gene expression in a manner similar to that seen after CNTF treatment. Leptin administration also suppressed NPY-induced feeding. However, peripheral and central CNTF injections markedly decreased leptin messenger RNA in lipocytes, indicating a deficiency of leptin in these rats; thus, leptin was unlikely to be involved in appetite suppression. Thus, these results show that a two-pronged central action of CNTF, causing diminution in both NPY availability and the NPY-induced feeding response, may underlie the severe anorexia. Further, unlike other members of the cytokine family, suppression of NPYergic signaling in the hypothalamus by CNTF does not involve up-regulation of leptin, but may involve a direct action on hypothalamic NPY neurons or on neural circuits that regulate NPY signaling in the hypothalamus.

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