Lipid Metabolism In Ovariectomized Rats Research Articles

Lactobacillus plantarum CCFM1180 attenuates obesity induced by estrogen deficiency by activating estrogen receptor alpha in abdominal adipose tissue and regulating gut microbiota-derived metabolitesestrogen

Lipid metabolism disorders commonly occur during menopause. Estrogen deficiency has been shown to lead to excessive energy intake and abnormal lipid metabolism in ovariectomized rats, resulting in obesity. Probiotics exhibit anti-obesity properties, and their underlying mechanism has been widely reported. In this study, we demonstrated the metabolic benefits of Lactobacillus plantarum CCFM1180 in suppressing appetite, controlling body weight, correcting obesity-induced abnormalities, enhancing liver lipid metabolism, and protecting liver function in estrogen-deficient rats. The mechanisms associated with the anti-obesity and anti-dyslipidemia effects of CCFM1180 on estrogen-deficient rats were clarified. The results showed that CCFM1180 dramatically reduced food intake by activating the expression of estrogen receptor alpha (ERα) and increasing the level of leptin in abdominal adipose tissue. These changes, combined with the increased butyrate concentration and recovered bile acid structure, helped enhance lipid metabolism. Additionally, CCFM1180 treatment was found to be safer than exogenous estrogen supplementation. Thus, L. plantarum CCFM1180 could be considered a new therapeutic strategy for preventing and alleviating menopausal lipid abnormalities.

Carya cathayensis Leaf Extract Exerts Estrogenic Effects on Hepatic Lipogenesis and Adipocytes Differentiation in Ovariectomized Rats Fed Normal or High-fat Diets

Our previous study has shown that total flavonoids from the leaves of C arya . cathayensis exert estrogenic activities by promoting the expressions of ERα, ERβ in vitro study. C. cathayensis leaf extract (CCE) was rich in flavonoids. Oral administration of CCE reduced the serum lipids and hepatic lipids, alleviated liver steatosis in ovariectomized rats. To investigate whether CCE has estrogenic effects on reproductive tissue and lipid metabolism in ovariectomized rats, and whether CCE has a direct effect on regulation of lipid synthesis and/or oxidation and adipocyte differentiation of ovariectomized (OVX) rats. Sprague–Dawley rats were ovariectomized and treated with CCE or estradiol in combination with a normal diet (ND), a high-fat diet (HFD) for 8 weeks. Histological analysis of uterus were performed and the lipid metabolism-related enzyme activity were examined. Expression of liver lipogenesis-related genes, adipocyte differentiation-and fat accumulation-related genes and protein were measured. Ovariectomy accelerated the uterine atrophy, development of dyslipidemia and hepatic steatosis, which were effectively mitigated by CCE supplementation. CCE significantly elevated ovariectomy-induced reduction in the cross-section area of the uterus and uterine glands. Compared with the OVX group, CCE increased the activities of lipoprtein lipase (LPL) and hepatic lipase (HL), decreased the hepatic mRNA expressions of Fas, Srebf1 , and Sla2a2 and increased Ppar α expressions at the mRNA levels under both ND and HFD conditions. CCE also decreased the Pck1 and G6pc mRNA expressions under HFD conditions, and show no significant effects on Hmgcr . The expressions of SREBP-1c, CEBPA and VEGF at the protein level were effectively regulated by CCE supplementation. CCE effectively alleviated ovariectomy-induced dyslipidemia and visceral fat accumulation by modulating hepatic lipogenesis and adipocyte differentiation. Furthermore, CCE exhibited estrogenic activity for the prevention of postmenopausal fatty liver.

The G-Protein-Coupled Estrogen Receptor Agonist Prevents Cardiac Lipid Accumulation by Stimulating Cardiac Peroxisome Proliferator-Activated Receptor α: A Preclinical Study in Ovariectomized-Diabetic Rat Model.

Type 2 diabetes mellitus (T2DM) is associated with cardiometabolic changes, and menopause exacerbates these conditions, leading to a greater risk of cardiovascular diseases (CVDs). The G protein-coupled estrogen receptor (GPER), which mediates the rapid effects of estrogen, has beneficial cardiac effects in both T2DM and menopause, but its mechanism of action is not well understood. This study aimed to determine whether G1 as a selective GPER-agonist has beneficial effects on cardiac lipid metabolism in ovariectomized rats with T2DM. Female Wistar rats were divided into 5 groups (n = 7 in each group): Sham-control (Sh-Ctl), T2DM, ovariectomized-T2DM (OVX-T2DM), OVX-T2DM-G1 (GPER-agonist), and OVX-T2DM-vehicle (OVX-T2DM-Veh). After stabilization of T2DM, G1 (200 μg/Kg) was administrated for 6 weeks. Then, the levels of free fatty acids (FFAs), CD36, peroxisome proliferator-activated receptor α (PPARα), and lipid accumulation in the cardiac tissue were determined. Compared with the Sh-Ctl group, cardiac FFAs (P < 0.001), CD36 (P < 0.05), and lipid accumulation (P < 0.001) increased, and cardiac PPARα (P < 0.01) decreased in T2DM animals; ovariectomy intensified these changes. Also, cardiac FFAs, PPARα, and lipid accumulation (P < 0.05) significantly decreased in the OVX-T2DM-G1 group compared to the OVX-T2DM-Veh group. However, cardiac CD36 levels did not change. G1 as a selective GPER-agonist affects lipid metabolism in T2DM animals. It also plays a vital role in improving cardiac metabolism during postmenopausal diabetic conditions.

Puerarin improves OVX-induced osteoporosis by regulating phospholipid metabolism and biosynthesis of unsaturated fatty acids based on serum metabolomics

BackgroundPostmenopausal osteoporosis (PMOP) is a serious problem for the women over 50 years old. Natural product puerarin (PUE) has been proven to improve PMOP with high safety. PMOP is a metabolic disorder affecting bone metabolism, indicating that endogenous metabolites amelioration may be a novel strategy for PMOP therapy. However, what the metabolic profile of POMP will be after PUE treatment is still obscure. PurposeWe purpose to figure out the metabolic characteristics of PMOP and to explore the intrinsic mechanism on the anti-osteoporosis efficacy after PUE treatment based on the serum metabolomics. MethodsWe established OVX rats as osteoporosis model, and the animals were distributed into Sham, OVX, and OVX+PUE (100 mg/kg/d) group. The femurs were analyzed by μ-CT and three-point bending test. Serum metabolomics was performed by UPLC/Q-TOF-MS. We also determined the body weight, liver weight, and the levels of serum TC, TG, LDL-C, and HDL-C. The key proteins of the PPARγ pathway and Wnt pathway were analyzed by Western blot and qPCR experiments. ResultsPUE treatment for 14 weeks both improved the bone structure and ameliorated lipid metabolism in ovariectomized rats. By determination and further analysis of serum metabolomics, we revealed that the endogenous metabolites was significantly changed in ovariectomized rats, and PUE treatment adjusted 23 differential metabolites, which were involved in phospholipid metabolism metabolism and PUFAs metabolic pathways. Close correlationships were futher found between the indexes of bone metabolism, lipid metabolism and the differential metabolites, particularly LysoPA, S1P and n-3/n-6 PUFAs. Further, we discovered that PUE regulated differentiation of BMSCs to elicit anti-osteoporosis efficacy, attributing to Wnt/β-catenin signaling activation and PPARγ pathway inhibition initiated by metabolomics. ConclusionPUE improves OVX-induced osteoporosis and lipid metabolism by regulating phospholipid metabolism and biosynthesis of PUFAs, resulting in reducing the adipogenic differentiation and promoting osteogenic differentiation of BMSCs via Wnt pathway activation and PPARγ pathway inhibition in ovariectomized rats. The study provides us a novel mechanism to explain the improvement of osteoporosis by PUE, depicts a metabolic profile of PMOP, and gives us another point cut for further exploring the pathogenesis of PMOP and looking for biomarkers of osteoporosis.

Agrimonia pilosa Ledeb. Ameliorates Hyperglycemia and Hepatic Steatosis in Ovariectomized Rats Fed a High-Fat Diet

Estrogen deficiency is associated with obesity, dyslipidemia, and increased insulin resistance in postmenopausal women. An efficient therapeutic agent prevents or improves postmenopausal conditions induced by estrogen deficiency. Here, we investigated the effects of aqueous Agrimonia pilosa Ledeb. extract on glucose and lipid metabolism in ovariectomized rats fed a high-fat diet (HFD). Female Sprague-Dawley rats were sham-operated or ovariectomized, and 3 weeks later were assigned to the following groups: sham-operated + HFD (S); ovariectomized + HFD (OVX); and ovariectomized + HFD with 0.5% A. pilosa aqueous extract (OVX + 0.5A) groups. Ovariectomy significantly increased body weight and dietary intake relative to the S group. However, A. pilosa treatment did not significantly affect weight gain or dietary intake. Blood triacylglycerol, total cholesterol, and low-density lipoprotein cholesterol levels tended to decrease in the A. pilosa-supplemented group. Blood glucose levels were significantly lower in the OVX + 0.5A group than those in the OVX group. Blood adiponectin and insulin concentrations increased significantly after A. pilosa treatment in the ovariectomized group. A. pilosa supplementation tended to decrease liver weights and prevented lipid accumulation. These effects correlated with reduced hepatic expression of lipogenesis-related genes (fatty acid synthase, acetyl-coenzyme A carboxylase alpha, and 3-hydroxy-3-methylglutaryl-coenzyme A reductase). Therefore, A. pilosa may improve metabolic disorders in ovariectomized rats.

Effect of Agrimonia Pilosa Ledeb. on glucose tolerance and hepatic steatosis in ovariectomized rats fed high fat diet

Estrogen deficiency is associated with obesity, dyslipidemia, and increased insulin resistance in postmenopausal women. Development of an efficient therapeutic agent without side effects is needed to prevent or improve postmenopausal symptoms and diseases induced by estrogen deficiency. This study was performed to investigate the effects of water extract from Agrimonia pilosa Ledeb. on glucose and lipid metabolism in ovariectomized rats fed high fat diet. Female Sprague Dawley rats were sham operated or ovariectomized and after 3 weeks, assigned to the following groups: sham‐operated + high fat diet(S); ovariectomized + high fat diet (OVX); ovariectomized + high fat diet with 0.1% A. pilosa water extract (OVX+0.1A); ovariectomized + high fat diet with 0.5% A. pilosa water extract (OVX+0.5A). In our results, ovariectomy significantly increased body weight and dietary intake compare with sham group (p&lt;0.05), however there was no significant difference in weight gain and dietary intake by A. pilosa treatment. Blood triglyceride, total‐cholesterol, and LDL‐cholesterol showed a tendency to decrease in A. pilosa supplemented groups. In glucose metabolism, we observed the blood glucose levels of the OVX+0.1A and OVX+0.5A groups were lower than those of the OVX group (p&lt;0.05). Blood adiponectin concentration was also increased significantly by A. pilosa treatment in ovariectomized group (p&lt;0.05). Additionally, we investigated the suppressive effect of A. pilosa aqueous extract on hepatic lipid accumulation. These effects were accompanied by reduced hepatic tissue expression of steatosis‐related genes. These data suggest that A. pilosa improves glucose tolerance and hepatic steatosis in ovariectomized rats.Support or Funding InformationThis study was supported by a research project of the National Institute of Agricultural Science of the Rural Development Administration, Republic of Korea (project no. PJ008554), and by the National Research Foundation of Korea(NRF) grant funded by the Korea government(MSIT) (No. 2017R1C1B5018328).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effect of olive leaf extract on the gene expression for lipid metabolism in ovariectomized rats (814.6)

There have not been enough studies regarding estrogen deficiency and lipid metabolism. Even though many postmenopausal women gain excess adipose tissues, the actual mechanism has not been yet fully understood. Thus, we measured mRNA expression after oral administration of olive leaf extract, which has been reported as an antioxidant, hepatoprotective, and hypolipidemic agent, in ovariectomized rats. Ovariectomized rats were administered either 200 or 400 mg/kg body weight of olive leaf extract (n=7 for each group) every day for 10 weeks. Expression of peroxisome proliferator‐activated receptor alpha and acyl‐CoA oxidase mRNA in the liver were significantly higher in the rats administered lower and higher dose of olive leaf extract compared with ovariectomized control. However, mRNA expression of liver carnitine palmitoyltransferase1a was not different among the groups. Expression of peroxisome proliferator activated receptor gamma mRNA in adipose tissue was decreased in the rats with 400 mg/kg body weight of olive leaf extract than ovariectomized control but it was not significantly different among the groups. Adipose triglyceride lipase expression and lipoprotein lipase mRNA did not change compared to ovariectomized control. These results suggest that genes involved in lipid metabolism may be regulated by olive leaf extract administration in ovariectomized rats. Transcription factors for further analyses to expand current results might include sterol regulatory element binding protein 1c and acetyl CoA carboxylase.

Genistein reduced insulin resistance index through modulating lipid metabolism in ovariectomized rats

Postmenopausal women are at higher risk for obesity and insulin resistance due to the decline of estrogen, but genistein, a phytoestrogen, may reduce the risks of these diet-related diseases. In this study, we hypothesized that supplemental genistein has beneficial effects on insulin resistance in an ovariectomized rat model by modulating lipid metabolism. Three weeks after a sham surgery (sham) or an ovariectomy (OVX), ovariectomized Sprague-Dawley rats were placed on a diet containing 0 (OVX group) or 0.1% genistein for 4 weeks. The sham rats were fed a high-fat diet containing 0% genistein and served as the control group (sham group). The ovariectomized rats showed increases in body weight and insulin resistance index, but genistein reduced insulin resistance index and the activity of hepatic fatty acid synthetase. Genistein was also associated with increased activity of succinate dehydrogenase and carnitine palmitoyltransferase and the rate of β-oxidation in the fat tissue of rats. The ovariectomized rats given genistein had smaller-sized adipocytes. Using gene-set enrichment analysis (GSEA) of microarray data, we found that a number of gene sets of fatty acid metabolism, insulin resistance, and oxidative stress were differentially expressed by OVX and reversed by genistein. This systemic approach of GSEA enables the identification of such consensus between the gene expression changes and phenotypic changes caused by OVX and genistein supplementation. Genistein treatment could help reduce insulin resistance through the amelioration of OVX-induced metabolic dysfunction, and the GSEA approach may be useful in proposing putative targets related to insulin resistance.

Effects of the estrogen antagonist EM-652.HCl on energy balance and lipid metabolism in ovariectomized rats.

The estrogen antagonist EM-652.HCl behaves as a highly potent and pure antiestrogen in human breast and uterine cancer cells. Because of its pure antiestrogenic activity in these cells, and because its prodrug, EM-800, reduces bone loss and decreases serum cholesterol and triglycerides in the rat, EM-652.HCl can be classified as a pure selective estrogen receptor modulator (SERM). This study was conducted to assess the ability of EM-652.HCl to prevent obesity and abnormalities of lipid metabolism induced by ovariectomy in a rat model. Female rats were left intact or ovariectomized (OVX), and OVX rats were treated with placebo, estradiol (E2), or EM-652.HCl for 20 days. At the end of the treatment period, parameters of energy balance and determinants of lipid metabolism were assessed. As expected, OVX increased energy intake, which in turn was accompanied by an increased energy, fat and protein gain and higher food efficiency. OVX also increased the triglyceride content of the liver and produced hypercholesterolemia and hyperinsulinemia. The weight of representative white adipose depots was higher in OVX than in intact rats. Lipoprotein lipase activity was higher in white adipose tissues of OVX rats than in those of intact animals, whereas its activity was lower in oxidative tissues (brown adipose and soleus muscle). Replacement therapy with a physiological dose of E2 prevented most of the abnormalities in energy and lipid metabolism brought about by OVX, although its orexigenic effect was only partially corrected. In contrast, treatment of OVX rats with EM-652. HCl completely abolished OVX-induced obesity and its related abnormalities in lipid metabolism and glucose/insulin homeostasis. These findings demonstrate that EM-652.HCl can be considered as an effective agent to prevent OVX-induced obesity. The present study also shows that EM-652.HCl reduces cardiovascular risk factors associated with obesity such as hyperlipidemia and insulin resistance.

Estrogen agonistic/antagonistic effects of miproxifene phosphate (TAT-59)

We evaluated miproxifene phosphate (TAT-59) to elucidate its efficacy in antiestrogen therapy for breast cancer patients and to assess its tissue-selective estrogenic/antiestrogenic activity. Using DP-TAT-59, a major and active metabolite of TAT-59, an in vitro cell growth inhibition test was performed. Antitumor activity was determined using TAT-59 against human tumor xenografts of the MCF-7 and the Br-10 cell lines and MCF-7-derived tamoxifen-resistant cell lines, R-27 and FST-1. The antitumor activity of DP-TAT-59 and DM-DP-TAT-59, major metabolites of TAT-59 found in human blood following a TAT-59 dose, was also examined after intravenous administration to experimental animals. The residual estrogenic activity of TAT-59, evaluated in terms of bone and lipid metabolism in ovariectomized rats, was then compared with that of tamoxifen. DP-TAT-59 significantly inhibited the proliferation of estrogen receptor-positive MCF-7 and T-47D tumor cells in the presence of 1 nM estradiol. TAT-59, given to mice bearing MCF-7 or Br-10 xenografts, at the dose level of 5 mg/kg, exerted a significant growth inhibitory effect that was stronger than that of tamoxifen. Moreover, R-27 and FST-1 tumors, which show a resistance to tamoxifen, responded strongly to TAT-59, suggesting that TAT-59 might be effective against tumors resistant to tamoxifen. The metabolites of TAT-59, DP-TAT-59 and DM-DP-TAT-59, showed similar antitumor activity. Both TAT-59 and tamoxifen suppressed the decrease in bone density and reduced the blood cholesterol levels in ovariectomized rats, suggesting that the estrogenic activity of TAT-59 is comparable to that of tamoxifen. On the basis of the above results, one may expect TAT-59 to become an effective drug in patients with tumors less sensitive to tamoxifen, while its estrogenic activity as determined by bone and lipid metabolism is similar to that of tamoxifen.