Long-Term Weight Cycling in Female Wistar Rats: Effects on Metabolism

LU, HUIQING, ANNE BUISON, VIRGINIA UHLEY AND K-L CATHERINE JEN. Long-term weight cycling in female Wistar rats: effects on metabolism. Obes Res. Weight cycling (WC) induced by ad-lib and restricted high fat (HF) feeding has been shown to reduce final body weight but not body fat percent in female Wistar rats. We examined the metabolic consequences of this type of WC. Five groups of female Wistar rats were fed a HF diet and the sixth group was fed a low fat diet to serve as a control group. Of the five HF groups, four groups were weight cycled by ad-lib and restricted feeding of the HF diet One of these groups weight cycled three times (HFCYC group) while the remaining three groups weight cycled once only, corresponding to the first, second and the third cycle of the HFCYC group. HF feeding induced hyperinsulinemia, hypertriglyceridemia, insulin resistance and elevated adipose tissue lipoprotein lipase (AT-LPL) activity levels as compared to rats fed the low fat (LF) control diet. WC further increased blood insulin concentrations and insulin resistance in rats with three cycles of WC. However, blood pressure was not affected by HF feeding or WC. The magnitude of increase of AT-LPL was reduced in weight cycled, HF fed obese rats after 15 weeks refeeding. We concluded that even though WC did not enhance weight gain nor impair weight loss, it did facilitate the development of insulin resistance and may predispose animals to diabetes.     

Fish Oil and the Pan-PPAR Agonist Tetradecylthioacetic Acid Affect the Amino Acid and Carnitine Metabolism in Rats

Peroxisome proliferator-activated receptors (PPARs) are important in the regulation of lipid and glucose metabolism. Recent studies have shown that PPARα-activation by WY 14,643 regulates the metabolism of amino acids. We investigated the effect of PPAR activation on plasma amino acid levels using two PPARα activators with different ligand binding properties, tetradecylthioacetic acid (TTA) and fish oil, where the pan-PPAR agonist TTA is a more potent ligand than omega-3 polyunsaturated fatty acids. In addition, plasma L-carnitine esters were investigated to reflect cellular fatty acid catabolism. Male Wistar rats (Rattus norvegicus) were fed a high-fat (25% w/w) diet including TTA (0.375%, w/w), fish oil (10%, w/w) or a combination of both. The rats were fed for 50 weeks, and although TTA and fish oil had hypotriglyceridemic effects in these animals, only TTA lowered the body weight gain compared to high fat control animals. Distinct dietary effects of fish oil and TTA were observed on plasma amino acid composition. Administration of TTA led to increased plasma levels of the majority of amino acids, except arginine and lysine, which were reduced. Fish oil however, increased plasma levels of only a few amino acids, and the combination showed an intermediate or TTA-dominated effect. On the other hand, TTA and fish oil additively reduced plasma levels of the L-carnitine precursor γ-butyrobetaine, as well as the carnitine esters acetylcarnitine, propionylcarnitine, valeryl/isovalerylcarnitine, and octanoylcarnitine. These data suggest that while both fish oil and TTA affect lipid metabolism, strong PPARα activation is required to obtain effects on amino acid plasma levels. TTA and fish oil may influence amino acid metabolism through different metabolic mechanisms.     

Valproic Acid Alters GnRH-GABA Interactions in Cycling Female Rats

Summary of the aims Women with epilepsy using antiepileptic drug valproic acid (VPA) often suffer from reproductive endocrine disorders, menstrual disorders and polycystic ovaries. Valproic acid exerts anticonvulsive effects via gamma amino butyric acid (GABA) neurotransmitter system, which also acts as a neurochemical regulator of gonadotropin-releasing hormone (GnRH) neurons and suggests possibility of valproic acid mediated interruption in gonadotropin releasing hormone pulse generator in hypothalamus. The aim of this study was to investigate the effects of valproic acid treatment on the expression of gonadotropin releasing hormone, gamma amino butyric acid and polysialylated form of neural cell adhesion molecule (PSA-NCAM) a marker of neuronal plasticity in the median preoptic area (mPOA) and median eminence-arcuate (ME-ARC) region having GnRH neuron cell bodies and axon terminals, respectively. Methods Three-month-old virgin Wistar strain female rats received VPA (i.p.) at a dose of 300 mg/kg once a day for 12 weeks; control group received an equivalent volume of vehicle. GnRH, GABA and PSA-NCAM expressions were studied by immunohistofluorescence technique from mPOA and ME-ARC region of hypothalamus. Ovarian histology was also studied using Mayer’s Haematoxylin-Eosin staining method. Results GnRH and PSA-NCAM staining was much higher in mPOA and ME-ARC region from vehicle treated control proestrous rats, whereas VPA treatment significantly enhanced GABA expression, and reduced both GnRH and PSA-NCAM expression. Mayer’s Haematoxylin-Eosin staining of mid-ovarian sections revealed significantly higher number of ovarian follicular cysts in VPA treated rats. Conclusions Our findings of alterations in GnRH and GABA expression and GnRH neuronal plasticity marker PSA-NCAM as well as changes in ovarian histology suggest that treatment with VPA disrupts hypothalamo-hypophyseal-gonadal axis (HPG) at the level of GnRH pulse generator in hypothalamus.     

Folic Acid Affects Iron Status in Female Rats with Deficiency of These Micronutrients

Biological Trace Element Research - Although simultaneous supplementation with iron and folic acid is justified, the potential interactions between these micronutrients are unknown. The aim of this...     

Prevention of Bone Growth Defects,Increased Bone Resorption and Marrow Adiposity with Folinic Acid in Rats Receiving Long-Term Methotrexate

The underlying pathophysiology for bone growth defects in paediatric cancer patients receiving high dose methotrexate chemotherapy remains unclear and currently there are no standardized preventative treatments for patients and survivors. Using a model in young rats, we investigated damaging effects of long-term treatment with methotrexate on growth plate and metaphyseal bone, and the potential protective effects of antidote folinic acid. This study demonstrated that chronic folinic acid supplementation can prevent methotrexate-induced chondrocyte apoptosis and preserve chondrocyte columnar arrangement and number in the growth plate. In the metaphysis, folinic acid supplementation can preserve primary spongiosa heights and secondary spongiosa trabecular volume by preventing osteoblasts from undergoing apoptosis and suppressing methotrexate-induced marrow adiposity and osteoclast formation. Systemically, plasma of folinic acid supplemented rats, in comparison to plasma from rats treated with MTX alone, contained a significantly lower level of IL-1β and suppressed osteoclast formation in vitro in normal bone marrow cells. The importance of IL-1β in supporting plasma-induced osteoclast formation was confirmed as the presence of an anti-IL-1β neutralizing antibody attenuated the ability of the plasma (from MTX-treated rats) in inducing osteoclast formation. Findings from this study suggest that folinic acid supplementation during chronic methotrexate treatment can alleviate growth plate and metaphyseal damages and therefore may be potentially useful in paediatric patients who are at risk of skeletal growth suppression due to chronic methotrexate chemotherapy.     

Effects of Long-Term Ayahuasca Administration on Memory and Anxiety in Rats

Ayahuasca is a hallucinogenic beverage that combines the action of the 5-HT_2A/2C agonist N,N-dimethyltryptamine (DMT) from Psychotria viridis with the monoamine oxidase inhibitors (MAOIs) induced by beta-carbonyls from Banisteriopsis caapi. Previous investigations have highlighted the involvement of ayahuasca with the activation of brain regions known to be involved with episodic memory, contextual associations and emotional processing after ayahuasca ingestion. Moreover long term users show better performance in neuropsychological tests when tested in off-drug condition. This study evaluated the effects of long-term administration of ayahuasca on Morris water maze (MWM), fear conditioning and elevated plus maze (EPM) performance in rats. Behavior tests started 48h after the end of treatment. Freeze-dried ayahuasca doses of 120, 240 and 480 mg/kg were used, with water as the control. Long-term administration consisted of a daily oral dose for 30 days by gavage. The behavioral data indicated that long-term ayahuasca administration did not affect the performance of animals in MWM and EPM tasks. However the dose of 120 mg/kg increased the contextual conditioned fear response for both background and foreground fear conditioning. The tone conditioned response was not affected after long-term administration. In addition, the increase in the contextual fear response was maintained during the repeated sessions several weeks after training. Taken together, these data showed that long-term ayahuasca administration in rats can interfere with the contextual association of emotional events, which is in agreement with the fact that the beverage activates brain areas related to these processes.     

戊巴比妥钠、水合氯醛、氨基甲酸乙酯麻醉对雌性SD大鼠血液学指标的影响

目的观察戊巴比妥钠、水合氯醛、氨基甲酸乙酯三种麻醉药物对雌性SD大鼠血液学指标的影响。方法选用戊巴比妥钠（40mg/kg）、水合氯醛（400mg/kg）、氨基甲酸乙酯（1g/kg）腹腔注射麻醉雌性SD大鼠,麻醉20min后眼眶静脉丛取血测定大鼠血液细胞学指标及血液生化指标。结果三种不同药物麻醉雌性SD大鼠20min后,某些血液细胞学指标及血液生化指标与生理盐水对照组相比均有不同程度的差异。结论麻醉药物可对雌性SD大鼠的血液学指标产生影响。     

Zoledronic Acid Treatment of Osteoporosis: Effects in Men

ObjectiveTo study changes in bone mineral density (BMD) and a bone resorption marker in elderly men who received off-label zoledronic acid for osteoporosis treatment.MethodsWe conducted a retrospective review of medical records of 50 male veterans who had received at least one 4-mg intravenous infusion of zoledronic acid and had BMD measurements at 2 of 3 skeletal sites both before the infusion and at a mean of 2.2 years after the infusion. Patients were classified into those who had never received bisphosphonate therapy versus those who had previously received such treatment.ResultsIn our study population, 66% of patients had been prescribed orally administered bisphosphonates or intravenously administered pamidronate before receiving zoledronic acid. Larger increases in spine BMD (6.7% versus 3.4% [P < .05]; per year: 2.8% versus 1.2% [P < .01]) and total hip BMD (3.2% versus 0.1% [P < .03]; per year: 1.3% versus 0.02% [P < .02]) occurred after infusion of zoledronic acid in bisphosphonate-naïve patients in comparison with those who had previous bisphosphonate exposure. In addition, 26 of 50 patients (52%) had suppressed urinary N-terminal telopeptide of cross-linked collagen type I (NTx) (a bone turnover marker) at 12 months, and 5 men had NTx suppression for 24 months after infusion.ConclusionOur data suggest that 4 mg of intravenously administered zoledronic acid is an effective treatment for increasing BMD in a “real-world” population of men with osteoporosis. The prolonged suppression of urinary NTx after zoledronic acid infusion raises the question of whether this treatment could be given less frequently than every year. The changes seen in BMD during a mean period of 2 years were similar to those reported in clinical studies with alendronate therapy in men and zoledronic acid treatment in women. (Endocr Pract. 2010;16:960-967)     

Treatment of Obese Female and Male SHHF/Mcc-facp Rats with Antihypertensive Drugs,Nifedipine and Enalapril: Effects on Body Weight,Fat Distribution,Insulin Resistance and Systolic Pressure

Little is known about the effects of common antihypertensive drugs in obese, insulin-resistant females. Nine-month-old obese female SHHF/Mcc-fn^cp rats that received either nifedipine, a calcium channel antagonist, or enalapril, an angiotensin-converting-enzyme inhibitor, for three months were compared with untreated SHHF/Mcc-fa^cp rats (controls). After one month, nifedipine significantly decreased body weight in obese females compared to either enalapril or controls. After three months of treatment, total, abdominal, and subcutaneous fat masses were decreased in obese females given nifedipine compared to either enalapril or controls. Enalapril treatment was associated with a redistribution of fat mass from abdominal to subcutaneous depots. Nifedipine reduced plasma triglyceride and fasting glucose levels and improved insulin response to an oral glucose load in obese females, whereas enalapril did not appear to affect glycemic control. Systolic pressure was not significantly decreased until after two months of treatment with nifedipine or three months of treatment with enalapril in obese females and may have coincided with improvement in insulin-resistance. Similarly, plasma atrial natriuretic peptide concentrations were significantly lower in obese females given nifedipine. To determine how obese males responded to a calcium channel antagonist, six-month-old obese male SHHF/Mcc-fa^cp rats were treated for three months with either nifedipine or placebo (controls). Nifedipine-treated obese males showed a mild but significant decrease in weight gain that was due to a decrease in fat deposition in both subcutaneous and abdominal depots and systolic blood pressure was significantly reduced after one month of treatment. Nifedipine did not affect other plasma biochemical parameters in obese males. In conclusion, nifedipine improved systolic pressure and glycemic control in obese female SHHI;/Mcc-fa^cp rats, effects that may be associated with a marked loss in body weight and fat mass and improved lipid metabolism. Nifedipine-treated obese males exhibited only a diminished weight gain that was not associated with changes in diabetic characteristics.     

C肽对糖尿病大鼠肾脏的影响

比较C肽和胰岛素对大鼠糖尿病肾病的治疗作用。方法:选取Wistar大鼠40只,分为正常对照组(NG组)和糖尿病组(DM组),糖尿病组链脲佐菌素诱发大鼠成模后,随机分为三组:糖尿病组(DM组)、胰岛素组(IG组)和C肽组(ICG组)。治疗8周后测定各组大鼠24小时尿白蛋白排泄率(UAER)、肾重/体重,并观察糖尿病大鼠肾脏超微结构变化。结果:24小时尿白蛋白排泄率:糖尿病组明显增加,C肽组明显低于糖尿病组和胰岛素组,差异具有显著性。大鼠肾脏超微结构变化:各组大鼠肾小球截面积、肾小球平均体积(MGV)、细胞外基质/肾小球截面积比值、细胞外基质截面积、肾小球基底膜厚度相比,糖尿病组明显升高,C肽组较胰岛素组和糖尿病组明显下降,差异具有显著性。结论:C肽治疗可以降低24小时尿白蛋白排泄率,改善糖尿病大鼠肾脏超微结构病变。     

Long-Term Treatment of Rats with Morphine Reduces the Activity of Messenger Ribonucleic Acid Coding for the β-Endorphin/ACTH Precursor in the Intermediate Pituitary

Abstract: Chronic administration of morphine to rats for a period of 4 weeks resulted in a 50-60% decrease in the tissue concentrations of β-endorphin and in the in vitro release from the neurointermediate pituitary. Incorporation of [³H]phenylalanine into isolated intermediate/posterior pituitaries in vitro revealed a reduction in the amount of label incorporated into the β-endorphin/ ACTH precursor to a similar extent (about 45%), but essentially no effect on the conversion of the precursor into β-lipotropin and β-endorphin. Extraction of mRNA from intermediate/posterior pituitaries followed by cell-free translation in a reticulocyte system showed no significant decrease in the total level of translatable mRNA. In contrast, the content of translatable mRNA coding for the β-endorphin/ACTH precursor was significantly reduced by 50-60%. Thus, long-term treatment with morphine appears to depress β-endorphin formation in the rat intermediate pituitary at the pretranslational level by markedly decreasing the activity of mRNA coding for the β-endorphin/ACTH precursor without any alteration in the processing of this precursor.     

Effects of Subchronic Aluminum Exposure on the Reproductive Function in Female Rats

The aim of this study was to investigate the effects of aluminum (Al) exposure on the reproductive function in female rats. Forty female Wistar (5 weeks old) rats, weighing 110–120 g, were divided randomly into four groups. They were orally administrated with 0, 64.18, 128.36, and 256.72 mg aluminum chloride (AlCl₃) per kilogram body weight in drinking water for 120 days. Levels of Al, estrogen (E₂), progestogen (P), testosterone (T), follicle-stimulating hormone (FSH), and luteinizing hormone (LH) in serum were measured at the end of experiment. The results showed that levels of E₂, P, FSH, and LH were significantly lower and Al concentration was significantly higher in all three Al-treated groups than those in the control group (GC). The level of T was significantly higher in the low- and medium-dose groups (GL and GM) (P < 0.05) but not in high-dose group (GH) compared with GC. The results suggest that the reproductive function of female rats is inhibited under long-term Al exposure in an Al dose-dependent manner.     

Ovarian Toxicity in Female Rats after Oral Administration of Melamine or Melamine and Cyanuric Acid

Although the toxicity of melamine to the kidneys and testes is well known, few studies have investigated the effects of melamine on female reproductive organs. Therefore, this study explores the effects of oral administration melamine or melamine and cyanuric acid for 28 days on the ovaries of female rats. Rats that were exposed to the mixture exhibited reduced ovarian and uterine weights, a shorter estrous cycle, and reduced serum estrogen and progesterone levels compared to rats that were exposed to melamine and control rats. Furthermore, morphological analysis revealed pathological changes in the ovaries of rats exposed to melamine or the mixture, such as more atretic follicles and necrosis of oocytes and granulosa cells. TUNEL staining revealed that the exposed groups had a higher proportion of TUNEL-positive granulosa cells than the control group, and the mRNA expressions of SOD1, GPX1, GPX2, P450scc, 17β-HSD I, and 17β-HSD II were reduced in the exposure groups compared with the control group. These results indicated that exposure to melamine alone or to the melamine-cyanuric acid mixture could damage the ovaries in rats.     

Altered Regulation of Akt Signaling with Murine Cerebral Malaria,Effects on Long-Term Neuro-Cognitive Function,Restoration with Lithium Treatment

Neurological and cognitive impairment persist in more than 20% of cerebral malaria (CM) patients long after successful anti-parasitic treatment. We recently reported that long term memory and motor coordination deficits are also present in our experimental cerebral malaria model (ECM). We also documented, in a murine model, a lack of obvious pathology or inflammation after parasite elimination, suggesting that the long-term negative neurological outcomes result from potentially reversible biochemical and physiological changes in brains of ECM mice, subsequent to acute ischemic and inflammatory processes. Here, we demonstrate for the first time that acute ECM results in significantly reduced activation of protein kinase B (PKB or Akt) leading to decreased Akt phosphorylation and inhibition of the glycogen kinase synthase (GSK3β) in the brains of mice infected with Plasmodium berghei ANKA (PbA) compared to uninfected controls and to mice infected with the non-neurotrophic P. berghei NK65 (PbN). Though Akt activation improved to control levels after chloroquine treatment in PbA-infected mice, the addition of lithium chloride, a compound which inhibits GSK3β activity and stimulates Akt activation, induced a modest, but significant activation of Akt in the brains of infected mice when compared to uninfected controls treated with chloroquine with and without lithium. In addition, lithium significantly reversed the long-term spatial and visual memory impairment as well as the motor coordination deficits which persisted after successful anti-parasitic treatment. GSK3β inhibition was significantly increased after chloroquine treatment, both in lithium and non-lithium treated PbA-infected mice. These data indicate that acute ECM is associated with abnormalities in cell survival pathways that result in neuronal damage. Regulation of Akt/GSK3β with lithium reduces neuronal degeneration and may have neuroprotective effects in ECM. Aberrant regulation of Akt/GSK3β signaling likely underlies long-term neurological sequelae observed in ECM and may yield adjunctive therapeutic targets for the management of CM.