Ameliorative effect of low-dose spironolactone on obesity and insulin resistance is through replenishment of estrogen in ovariectomized rats

2019 ◽  
Vol 97 (1) ◽  
pp. 65-74 ◽  
Author(s):  
Lawrence A. Olatunji ◽  
Oluwaseun A. Adeyanju ◽  
Olugbenga S. Michael ◽  
Taofeek O. Usman ◽  
Rita C. Tostes ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Low Dose ◽  
Glycogen Synthase ◽  
Mass Gain ◽  
Ovariectomized Rats ◽  
Atherogenic Dyslipidemia ◽  
Beneficial Effects ◽  
Ovx Rats ◽  
Ameliorative Effect ◽  
Hormonal Therapies

Women have a lower incidence of cardiovascular diseases (CVD) than men at a similar age but the reverse is the case after menopause, indicating a possible protective effect of estrogen on cardiometabolic function. Although various hormonal therapies have been formulated to combat the CVD risks in postmenopausal state, the beneficial effects have not been consistent. Obesity with insulin resistance (IR) is closely linked to CVD risks while ovariectomized rodents have been shown to mimic a state of obesity and IR. We therefore hypothesized that low-dose spironolactone would ameliorate obesity and IR in estrogen-deprived rats by replenishing estrogen and suppressing elevated glycogen synthase kinase-3 (GSK-3). Ten-week-old female Wistar rats were divided into 4 groups: sham-operated (SHM), spironolactone (SPL; 0.25 mg/kg), and ovariectomized (OVX) rats treated with or without spironolactone daily for 8 weeks. Results showed that estrogen deprivation through ovariectomy caused increased body mass gain and visceral adiposity that are accompanied by increased HOMA-IR, HOMA-β, 1-hour postload glucose, glucose intolerance, platelet/lymphocyte ratio, plasma insulin, atherogenic dyslipidemia, uric acid, GSK-3, corticosterone, and aldosterone and depressed 17β-estradiol. However, treatment of OVX rats with spironolactone ameliorated all these effects. Taken together, the results demonstrate that treatment with low-dose spironolactone improves obesity and IR, which appears to involve replenishment of estrogen and suppression of GSK-3 along with circulating mineralocorticoid and glucocorticoid. The findings imply a positive cardiometabolic effect of low-dose spironolactone usage in estrogen-deprived conditions.

scholarly journals Oral hormonal therapy with ethinylestradiol–levonorgestrel improves insulin resistance, obesity, and glycogen synthase kinase-3 independent of circulating mineralocorticoid in estrogen-deficient rats

2018 ◽  
Vol 96 (6) ◽  
pp. 577-586 ◽  
Author(s):  
Oluwaseun A. Adeyanju ◽  
Olaniyi A. Soetan ◽  
Ayodele O. Soladoye ◽  
Lawrence A. Olatunji
Keyword(s):  
Insulin Resistance ◽  
Hormonal Therapy ◽  
Cell Function ◽  
Glycogen Synthase ◽  
Hdl Cholesterol ◽  
Glycogen Synthase Kinase ◽  
Ovariectomized Rats ◽  
Glycogen Synthase Kinase 3 ◽  
Model Assessment ◽  
Ovx Rats

Estrogen deficiency has been associated with increased incidence of cardiovascular diseases , and recent clinical trials of standard formulations of hormonal therapies have not demonstrated consistent beneficial effects. Estrogen–progestin therapy has been used as exogenous estrogen to normalize depressed estrogen level during menopause. Ovariectomized rodents mimic an estrogen-deficient state in that they develop cardiometabolic dysfunction, including insulin resistance (IR). We therefore hypothesized that hormonal therapy with combined oral contraceptive steroids, ethinylestradiol–levonorgestrel (EEL), improves IR, obesity, and glycogen synthase kinase-3 (GSK-3) through reduction of circulating mineralocorticoid in ovariectomized rats. Twelve-week-old female Wistar rats were divided into 4 groups: sham-operated (SHM) and ovariectomized (OVX) rats were treated with or without EEL (1.0 μg ethinylestradiol and 5.0 μg levonorgestrel) daily for 8 weeks. Results showed that OVX or SHM + EEL treated rats had increased HOMA-IR (homeostatic model assessment of IR), 1 h postload glucose, HOMA-β, triglycerides (TG), total cholesterol (TC), TC/HDL cholesterol, TG/HDL cholesterol, plasma insulin, GSK-3, corticosterone, and aldosterone. On the other hand, OVX + EEL treatment ameliorated all these effects except that of aldosterone. Taken together, the results demonstrate that oral hormonal replacement with EEL improves IR and pancreatic β-cell function and suppresses GSK-3 and glucocorticoid independent of circulating aldosterone, suggesting a positive cardiometabolic effect of oral EEL therapy in estrogen-deficient rats.

scholarly journals Combination treatment with pioglitazone and fenofibrate attenuates pioglitazone-mediated acceleration of bone loss in ovariectomized rats

2011 ◽  
Vol 212 (2) ◽  
pp. 179-186 ◽  
Author(s):  
Rana Samadfam ◽  
Malaika Awori ◽  
Agnes Bénardeau ◽  
Frieder Bauss ◽  
Elena Sebokova ◽  
...  
Keyword(s):  
Bone Loss ◽  
Bone Mass ◽  
Trabecular Bone ◽  
Bone Mineral ◽  
Combination Treatment ◽  
Mass Gain ◽  
Ovariectomized Rats ◽  
Concomitant Treatment ◽  
Mineral Density ◽  
Ovx Rats

Peroxisome proliferator-activated receptor (PPAR) γ agonists, such as pioglitazone (Pio), improve glycemia and lipid profile but are associated with bone loss and fracture risk. Data regarding bone effects of PPARα agonists (including fenofibrate (Feno)) are limited, although animal studies suggest that Feno may increase bone mass. This study investigated the effects of a 13-week oral combination treatment with Pio (10 mg/kg per day)+Feno (25 mg/kg per day) on body composition and bone mass parameters compared with Pio or Feno alone in adult ovariectomized (OVX) rats, with a 4-week bone depletion period, followed by a 6-week treatment-free period. Treatment of OVX rats with Pio+Feno resulted in ∼50% lower fat mass gain compared with Pio treatment alone. Combination treatment with Pio+Feno partially prevented Pio-induced loss of bone mineral content (∼45%) and bone mineral density (BMD; ∼60%) at the lumbar spine. Similar effects of treatments were observed at the femur, most notably at sites rich in trabecular bone. At the proximal tibial metaphysis, concomitant treatment with Pio+Feno prevented Pio exacerbation of ovariectomy-induced loss of trabecular bone, resulting in BMD values in the Pio+Feno group comparable to OVX controls. Discontinuation of Pio or Feno treatment of OVX rats was associated with partial reversal of effects on bone loss or bone mass gain, respectively, while values in the Pio+Feno group remained comparable to OVX controls. These data suggest that concurrent/dual agonism of PPARγ and PPARα may reduce the negative effects of PPARγ agonism on bone mass.

scholarly journals Vitex agnus-castusL. (Verbenaceae) Improves the Liver Lipid Metabolism and Redox State of Ovariectomized Rats

2015 ◽  
Vol 2015 ◽  
pp. 1-14 ◽  
Author(s):  
Franciele Neves Moreno ◽  
Lilian Brites Campos-Shimada ◽  
Silvio Claudio da Costa ◽  
Rosângela Fernandes Garcia ◽  
Alessandra Lourenço Cecchini ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Liver Lipid ◽  
Redox Status ◽  
Ovariectomized Rats ◽  
Beneficial Effects ◽  
Ovx Rats ◽  
Agnus Castus ◽  
General Improvement ◽  
The Central Nervous System ◽  
Fat Liver

Vitex agnus-castus(VAC) is a plant that has recently been used to treat the symptoms of menopause, by its actions on the central nervous system. However, little is known about its actions on disturbances in lipid metabolism and nonalcoholic fat liver disease (NAFLD), frequently associated with menopause. Ovariectomized (OVX) rats exhibit increased adiposity and NAFLD 13 weeks after ovary removal and were used as animal models of estrogen deficiency. The rats were treated with crude extract (CE) and a butanolic fraction of VAC (ButF) and displayed the beneficial effects of a reduction in the adiposity index and a complete reversion of NAFLD. NAFLD reversion was accompanied by a general improvement in the liver redox status. The activities of some antioxidant enzymes were restored and the mitochondrial hydrogen peroxide production was significantly reduced in animals treated with CE and the ButF. It can be concluded that the CE and ButF fromVitex agnus-castuswere effective in preventing NAFLD and oxidative stress, which are frequent causes of abnormal liver functions in the postmenopausal period.

High-impact exercise strengthens bone in osteopenic ovariectomized rats with the same outcome as Sham rats

2003 ◽  
Vol 95 (3) ◽  
pp. 1032-1037 ◽  
Author(s):  
Akiko Honda ◽  
Naota Sogo ◽  
Seigo Nagasawa ◽  
Takuya Shimizu ◽  
Yoshihisa Umemura
Keyword(s):  
Bone Mass ◽  
Female Rats ◽  
Ovariectomized Rats ◽  
Middle Aged ◽  
Mineral Density ◽  
Beneficial Effects ◽  
Ovx Rats ◽  
Jump Exercise ◽  
Body Weights ◽  
The Right

The effect of jump exercise on middle-aged osteopenic rats was investigated. Forty-two 9-mo-old female rats were either sham-operated (Sham) or ovariectomized (OVX). Three months after surgery, the rats were divided into the following groups: Sham sedentary, Sham exercised, OVX sedentary, and OVX exercised. Rats in the exercise groups jumped 10 times/day, 5 days/wk, for 8 wk, with a jumping height of 40 cm. Less than 1 min was required for the jump training. After the experiment, the right tibia and femur were dissected, and blood was obtained from each rat. OVX rats were observed to have increased body weights and decreased bone mass in their tibiae and femurs. Jump-exercised rats, on the other hand, had significantly increased tibial bone mass, strength, and cortical areas. The bone mass and strength of OVX exercised rats increased to approximately the same extent as Sham exercised rats, despite estrogen deficiency or osteopenia. Our data suggest that jump exercise has beneficial effects on lower limb bone mass, strength, bone mineral density, and morphometry in middle-aged osteopenic rats, as well as in Sham rats.

scholarly journals Beneficial Effects of Total Phenylethanoid Glycoside Fraction Isolated from Cistanche deserticola on Bone Microstructure in Ovariectomized Rats

2019 ◽  
Vol 2019 ◽  
pp. 1-13 ◽  
Author(s):  
Lingling Yang ◽  
Shuqin Ding ◽  
Bo Zhang ◽  
Jingjing Liu ◽  
Yanhong Dong ◽  
...  
Keyword(s):  
Signaling Pathways ◽  
Bone Microarchitecture ◽  
Bone Microstructure ◽  
Akt Signaling ◽  
Hplc Method ◽  
Ovariectomized Rats ◽  
Mineral Density ◽  
Phenylethanoid Glycoside ◽  
Beneficial Effects ◽  
Ovx Rats

The present study was designed to estimate the antiosteoporotic activity of total phenylethanoid glycoside fraction isolated from C. deserticola (CDP) on rats induced by ovariectomy (OVX) as well as the related mechanisms. After 3 months of oral administration, the decreased bone mineral density, serum Ca, and P in OVX rats were recovered and the deteriorated trabecular bone microarchitecture was partly improved by CDP (60, 120, and 240 mg/kg) intervention, the activities of bone resorption markers were downregulated, and the bioactive of the bone formation index was upregulated; meanwhile, the content of MDA was declined, and GSH was increased by CDP treatment. Compositionally, 8 phenylethanoid glycoside compounds were identified in CDP, with the total contents quantified as 50.3% by using the HPLC method. Mechanistically, CDP declined the levels of TRAF6, RANKL, and RANK, thus suppressing RANKL/RANK/TRAF6-induced activation of downstream NF-κB and PI3K/AKT signaling pathways and ultimately preventing activities of the key osteoclastogenic proteins of NFAT2 and c-Fos. All of the above data implied that CDP exhibited beneficial effects on bone microstructure in ovariectomized rats, and these effects may be related to the NF-κB and PI3K/AKT signaling pathways which were triggered by the binding of RANKL, RANK, and TRAF6.

Effect of exercise training on cardiac oxytocin and natriuretic peptide systems in ovariectomized rats

2007 ◽  
Vol 293 (1) ◽  
pp. R267-R275 ◽  
Author(s):  
Jolanta Gutkowska ◽  
Amélie Paquette ◽  
Donghao Wang ◽  
Jean-Marc Lavoie ◽  
Marek Jankowski
Keyword(s):  
Exercise Training ◽  
Natriuretic Peptide ◽  
Ovariectomized Rats ◽  
Inos Mrna ◽  
Chronic Exercise ◽  
Fat Pad ◽  
Beneficial Effects ◽  
Ovx Rats ◽  
The Right ◽  
Response To Exercise

Exercise training results in cardiovascular and metabolic adaptations that may be beneficial in menopausal women by reducing blood pressure, insulin resistance, and cholesterol level. The adaptation of the cardiac hormonal systems oxytocin (OT), natriuretic peptides (NPs), and nitric oxide synthase (NOS) in response to exercise training was investigated in intact and ovariectomized (OVX) rats. Ovariectomy significantly augmented body weight (BW), left ventricle (LV) mass, and intra-abdominal fat pad weight and decreased the expression of oxytocin receptor (OTR), atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and guanylyl cyclase-A (GC-A), in the right atrium (RA) and LV, indicating estrogenic control of these genes. These effects of ovariectomy were counteracted by 8-wk-long exercise training which decreased fat pad weight (33.4 ± 2.3 to 23.4 ± 3.1 g, n = 8, P < 0.05), plasma free fatty acids (0.124 ± 0.033 to 0.057 ± 0.010 mM, n = 8, P < 0.01), and plasma triacylglycerol (0.978 ± 0.174 to 0.588 ± 0.115 mM, n = 8, P < 0.05). Chronic exercise tended to decrease BW and stimulated ANP (4- to 5-fold) and OTR gene expression in the LV and RA and BNP and inducible NOS (iNOS) mRNA in the LV. In sham-operated rats, exercise augmented ANP expression in the RA, downregulated GC-A mRNA in the LV and RA, but increased its expression threefold in the RA of OVX animals. Endothelial NOS and iNOS expression was enhanced in the left atrium of sham-operated rats. Altogether, these data indicate that in OVX animals, chronic exercise significantly enhances cardiac OT, NPs, and NOS, thus implicating all three hormonal systems in the beneficial effects of exercise training.

scholarly journals Prenylated Isoflavonoids-Rich Extract of Erythrinae Cortex Exerted Bone Protective Effects by Modulating Gut Microbial Compositions and Metabolites in Ovariectomized Rats

Nutrients ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2943
Author(s):  
Hui-Hui Xiao ◽  
Xueli Yu ◽  
Chen Yang ◽  
Chi-On Chan ◽  
Lu Lu ◽  
...  
Keyword(s):  
Bone Microarchitecture ◽  
Cathepsin K ◽  
Short Chain Fatty Acids ◽  
Female Rats ◽  
Ovariectomized Rats ◽  
Protective Effects ◽  
Sprague Dawley ◽  
Mineral Density ◽  
Beneficial Effects ◽  
Ovx Rats

Flavonoids, found in a wide variety of foods and plants, are considered to play an important role in the prevention and treatment of osteoporosis. Our previous studies demonstrated that Erythrina cortex extract (EC) rich in prenylated isoflavonoids exerted bone protective effects in ovariectomized (OVX) rats. The present study aimed to investigate the interactions of gut microbiota with the EC extract to explore the underlying mechanisms involved in its beneficial effects on bone. Sprague-Dawley female rats of 3-months-old were ovariectomized and treated with EC extract for 12 weeks. EC extract reversed ovariectomy-induced deterioration of bone mineral density and bone microarchitecture as well as downregulated cathepsin K (Ctsk) and upregulated runt-related transcription factor 2 (Runx2) and alkaline phosphatase (ALP) in the tibia of OVX rats. Its protective effects on bone were correlated with changes in microbial richness and the restorations of several genera. EC increased the serum circulating levels of acetate and propionate in OVX rats. We conclude that the bone protective effects of EC extract were associated with the changes in microbial compositions and serum short chain fatty acids (SCFAs) in OVX rats.

scholarly journals Raloxifene Ameliorates Glucosamine-Induced Insulin Resistance in Ovariectomized Rats

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1114
Author(s):  
Chung-Hwan Chen ◽  
Tsung-Lin Cheng ◽  
Chi-Fen Chang ◽  
Hsuan-Ti Huang ◽  
Sung-Yen Lin ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Estrogen Receptor ◽  
Er Stress ◽  
Postmenopausal Women ◽  
Ovariectomized Rats ◽  
Protective Effects ◽  
Β Cell ◽  
Cell Dysfunction ◽  
Induce Insulin Resistance ◽  
Ovx Rats

Osteoarthritis (OA) and osteoporosis (OP) are common among older women, especially postmenopausal women. Glucosamine (GlcN) is a common medication for OA, but it may induce insulin resistance and β-cell dysfunction, especially if ovarian hormones are lacking. Raloxifene (RLX) is a selective estrogen receptor modulator and also an OP drug. Previously, we found that estrogen could improve GlcN-induced insulin resistance in ovariectomized (OVX) rats. Here, we further hypothesized that RLX, similarly to estrogen, can ameliorate GlcN-induced insulin resistance in OVX rats. We used GlcN to induce insulin resistance in OVX rats as a model for evaluating the protective effects of RLX in vivo. We used a pancreatic β-cell line, MIN-6, to study the mechanisms underlying the effect of RLX in GlcN-induced β-cell dysfunction in vitro. Increases in fasting plasma glucose, insulin, and homeostasis model assessments of insulin resistance in OVX Sprague Dawley rats treated with GlcN were reversed by RLX treatment (n = 8 in each group). Skeletal muscle GLUT-4 increased, liver PEPCK decreased, pancreatic islet hypertrophy, and β-cell apoptosis in OVX rats treated with GlcN was ameliorated by RLX. The negative effects of GlcN on insulin secretion and cell viability in MIN-6 cells were related to the upregulation of reticulum (ER) stress-associated proteins (C/EBP homologous protein, phospho-extracellular signal-regulated kinase, phospho-c-JunN-terminal kinase), the expression of which was reduced by RLX. Pretreatment with estrogen receptor antagonists reversed the protective effects of RLX. GlcN can induce insulin resistance, β-cell dysfunction, and apoptosis in OVX rats and increase ER stress-related proteins in β-cells, whereas RLX can reverse these adverse effects. The effects of RLX act mainly through estrogen receptor α; therefore, RLX may be a candidate drug for postmenopausal women with OA and OP.

Low-intensity exercise in the prevention of cardiac insulin resistance-related inflammation and disturbances in NOS and MMP-9 regulation in fructose-fed ovariectomized rats

2019 ◽  
Vol 44 (11) ◽  
pp. 1219-1229 ◽  
Author(s):  
Jelena Stanisic ◽  
Goran Koricanac ◽  
Milan Kostic ◽  
Mojca Stojiljkovic ◽  
Tijana Culafic ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Signaling ◽  
Insulin Level ◽  
Ovariectomized Rats ◽  
Model Assessment ◽  
Homa Index ◽  
Low Intensity ◽  
Ovx Rats ◽  
Tnf Α ◽  
Low Intensity Exercise

Exercise is important nonpharmacological treatment for improvement of insulin sensitivity in menopause. However, its effect on menopausal cardiac insulin resistance is needing further research. We investigated protective effects of low-intensity exercise on cardiac insulin signaling, inflammation, regulation of nitric oxide synthase (NOS) and matrix metalloproteinase 9 (MMP-9) in ovariectomized (OVX) Wistar rats, submitted to 10% fructose solution for 9 weeks. OVX rats were divided into control, sedentary fructose, and exercise fructose groups. Measurements of physical and biochemical characteristics were carried out to evaluate metabolic syndrome development. Messenger RNA and protein levels and phosphorylation of cardiac insulin signaling molecules, endothelial and inducible NOS (eNOS and iNOS), p65 subunit of nuclear factor κB (NFκB), tumor necrosis factor α (TNF-α), suppressor of cytokine signaling 3 (SOCS3), and MMP-9 were analyzed. Fructose increased insulin level, homeostasis model assessment (HOMA) index, and visceral adipose tissue weight, while low-intensity exercise prevented insulin level and HOMA index increase. Fructose also decreased cardiac pAkt (Ser473), peNOS (Ser1177) and increased insulin receptor substrate 1 (IRS1) phosphorylation at Ser307, pNFκB (Ser276) and NFκB and MMP-9 content, without any effect on iNOS, protein-tyrosine phosphatase 1B, TNF-α, and SOCS3. Exercise prevented changes in pIRS1 (Ser307), pAkt (Ser473), peNOS (Ser1177), pNFκB (Ser276), and NFκB expression. In addition, exercise increased pIRS1 (Tyr632), pAkt (Thr308), and eNOS expression. Low-intensity exercise prevented cardiac insulin signaling disarrangement in fructose-fed OVX rats and therefore eNOS dysfunction, as well as pro-inflammatory signaling activation, without effect on tissue remodeling, suggesting physical training as a way to reduce cardiovascular risk.

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