Long-term administration of olanzapine induces adiposity and increases hepatic fatty acid desaturation protein in female C57BL/6J mice

Objective(s): Weight gain and metabolic disturbances such as dyslipidemia, are frequent side effects of second-generation antipsychotics, including olanzapine. This study examined the metabolic effects of chronic olanzapine exposure. In addition, we investigated the hepatic fatty acid effects of olanzapine in female C57BL/6J mice fed a normal diet.Materials and Methods: Female C57BL/6J mice orally received olanzapine or normal saline for 7 weeks. The effects of long-term olanzapine exposure on body weight changes, food efficiency, blood glucose, triglyceride (TG), insulin, and leptin levels were observed. Hepatic TG and abdominal fat mass were investigated, and fat cell morphology was analyzed through histopathological methods. The levels of protein markers of fatty acid regulation in the liver, namely fatty acid synthase (FAS) and stearoyl-CoA desaturase-1 (SCD-1), were measured.Results: Olanzapine treatment increased the food intake of the mice as well as their body weight. Biochemical analyses showed that olanzapine increased blood TG, insulin, leptin, and hepatic TG. The olanzapine group exhibited increased abdominal fat mass and fat cell enlargement in abdominal fat tissue. Western blotting of the mouse liver revealed significantly higher (1.6-fold) levels of SCD-1 in the olanzapine group relative to the control group; by contrast, FAS levels in the two groups did not differ significantly.Conclusion: Enhanced lipogenesis triggered by increased hepatic SCD-1 activity might be a probable peripheral mechanism of olanzapine-induced dyslipidemia. Some adverse metabolic effects of olanzapine may be related to the disturbance of lipid homeostasis in the liver

Curcumin Improved Glucose Intolerance, Renal Injury, and Nonalcoholic Fatty Liver Disease and Decreased Chromium Loss through Urine in Obese Mice

Obesity-associated hyperglycemia underlies insulin resistance, glucose intolerance, and related metabolic disorders including type 2 diabetes, renal damage, and nonalcoholic fatty liver disease. Turmeric root is commonly used in Asia, and curcumin, one of its pharmacological components, can play a role in preventing and treating certain chronic physiological disorders. Accordingly, this study examined how high-fat diet (HFD)-induced hyperglycemia and hyperlipidemia are reduced by curcumin through changes in fatty liver scores, chromium distribution, and renal injury in mice. Relative to the control group, also fed an HFD, the curcumin group weighed less and had smaller adipocytes; it also had lower daily food efficiency, blood urea nitrogen and creatinine levels, serum alanine aminotransferase and aspartate aminotransferase levels, serum and hepatic triglyceride levels, and hepatic lipid regulation marker expression. The curcumin-treated obese group exhibited significantly lower fasting blood glucose, was less glucose intolerant, had higher Akt phosphorylation and glucose transporter 4 (GLUT4) expression, and had greater serum insulin levels. Moreover, the group showed renal damage with lower TNF-α expression along with more numerous renal antioxidative enzymes that included superoxide dismutase, glutathione peroxidase, and catalase. The liver histology of the curcumin-treated obese mice showed superior lipid infiltration and fewer FASN and PNPLA3 proteins in comparison with the control mice. Curcumin contributed to creating a positive chromium balance by decreasing the amount of chromium lost through urine, leading to the chromium mobilization needed to mitigate hyperglycemia. Thus, the results suggest that curcumin prevents HFD-induced glucose intolerance, kidney injury, and nonalcoholic fatty liver disease

Study of the blockage effect of rapamycin in high fat diet-induced obesity mice

雷帕黴素是由土壤中細菌- Streptomyces hygroscopicus分離出的一種抗黴菌藥，它同時也是mTOR的專一性抑制劑。由於雷帕黴素具有免疫抑制的特性，因此，近年來，雷帕黴素常廣泛使用於器官移植後，做為抗排斥藥物。雖然，已有文獻發現雷帕黴素具有抑制脂肪細胞分化的作用，然而，雷帕黴素對於是否具抗肥胖的效果仍不是十分清楚。本論文分別利用C57BL/6J及KK/HlJ 等2種不同品係的肥胖動物模式小鼠，探討雷帕黴素對於代謝的影響。肥胖C57BL/6J小鼠以雷帕黴素每週2 mg/kg劑量連續16週腹腔注射後，發現有體重、副睪脂肪重量減輕，減少每日飼料效率，血中瘦體素及胰島素濃度下降之情形。然而，雷帕黴素卻會增加C57BL/6J小鼠的食物攝取量，並且對於禁食血糖沒有顯著的影響。組織形態學分析每週一次腹腔注射雷帕黴素的C57BL/6J小鼠，其脂肪肝程度、脂肪細胞形態、大型後腹腔脂肪細胞和大型副睪脂肪細胞的比例皆顯著減小。於第二型糖尿病特徵KK/HlJ小鼠則改以雷帕黴素每天2 mg/kg劑量連續42天腹腔注射，結果發現雷帕黴素在KK/HlJ小鼠同樣具有抗肥胖效果。然而，注射雷帕黴素KK/HlJ小鼠即使有較高的胰島素濃度，但雷帕黴素卻會增加活性氧自由基的濃度，同時並造成KK/HlJ小鼠葡萄糖耐受性不良。綜合上述，雷帕黴素藉由減少脂肪蓄積而對抗高脂飲食會增加體重的效果，因此，雷帕黴素可用於體重控制和防止肥胖的發生，但長期、高頻率地使用雷帕黴素，仍需考慮其影響血糖恆定的副作用，特別是當用於高胰島素血症和葡萄糖耐受性不良之情形。Rapamycin (RAPA), an anti-fungal macrolide, is an unique and specific mTOR kinase inhibitor isolated from soil bacterium, Streptomyces hygroscopicus. Subsequently, RAPA was shown to have potent immunosuppressive and antiproliferative effects. As an immunosuppressant drug, it is used extensively to prevent graft rejection in transplant patients. Although, it has been reported to inhibit adipogenesis in vitro, however, the full extent of the role of RAPA in treating human/animal obesity has not been fully explored. In this study, we investigated the metabolic effects of RAPA in two different obese animal models, C57BL/6J and KK/HlJ mice. The high fat diet-fed (HFD) C57BL/6J mice were injected intraperitoneally with RAPA (2 mg/kg/week for 16 weeks) had reduced body weight and epididymal fat pads/body weight, reduced daily food efficiency, and lower serum leptin and insulin levels compared with the HFD control mice. However, RAPA-treated mice were hyperphagic, demonstrating an increase in food intake and exhibited similar blood glucose levels relative to the control group. Dissection of RAPA-treated mice revealed a marked reduction in fatty liver scores, average fat cell size and percentage of large adipocytes of retroperitoneal and epididymal white adipose tissue (RWAT and EWAT), compared to the HFD control mice. On the other hand, obese KK/HlJ mice were treated with a daily intraperitoneal injection of RAPA at 2 mg/kg or vehicle for 42 days on a HFD. Treated KK/HlJ mice also exhibited the pronounced anti-obesity effects of RAPA in metabolic parameters based on histological and image analysis. However, RAPA-treated animals showed a marked decline in glucose tolerance as judged by the 180-minute area under the curve for plasma glucose levels, paralleled by increased generation of plasma reactive oxygen species (ROS), despite greater serum insulin levels. Tthese results suggest that RAPA preventsthe effect of a high fat diet on the rate of accretion in body weight via reducing lipid accumulation. It is likely that RAPA may serve as a potential strategy for body weight control and/or anti-obesity, while prolonged and continual use of RAPA can cause adverse effects such as the deterioration of blood glucose homeostasis, especially in conditions with hyperinsulinemia and glucose intolerance.中文摘要 ……………………………………………………………4 英文摘要 ……………………………………………………………5 目錄.................................................. 7 圖次.................................................. 9 表次.................................................. 10 第一章 緒言………………………………....................11 第一節 前言…………………………………………………......11 第二節 文獻回顧………………………………………………....14 一、肥胖 …………………………………………………… 14 （一）肥胖成因及定義 ………….………………….... 14 （二）肥胖對健康的危害 ………………...………… 15 二、mTOR ………………………………….……………… 21 （一）mTOR途徑訊息傳遞 ………………………... 22 （二）mTOR與代謝性疾病、癌症、炎症關係 …… 26 三、免疫抑制劑 ……………………….………………….. 29 四、雷帕黴素臨床應用之未來性…………………….…… 34 第三節 研究假說與設計…..………..………………….……… 38 第二章 雷帕黴素改善高脂飲食誘導C57BL/6J小鼠的肥胖......40 第一節 前言…………………………………………………... 40 第二節 材料和方法 ……………………………………………. 41 第三節 結果…………………..………………………………. 43 第四節 討論………………………………………………….. 46 第三章 長期使用雷帕黴素可減少高脂餵食KK/HlJ小鼠的 肥胖，但會造成小鼠葡萄糖耐受性不良 ………………. 56 第一節 前言…………………………………………………... 56 第二節 材料和方法 ……………………………………………. 57 第三節 結果…………………..………………………………. 61 第四節 討論………………………………………………….. 65 第四章 結論……..……………………………………………. 76 參考文獻 ……………………………………………………… 79 附錄………………………………………………...... 10

Study of Annual Fluctuations of Fecal Reproductive Steroids in Formosan Black Bears (Ursus thibetanus formosanus)

本研究應用非侵入性之酵素免疫分析法，對6隻圈養在特有生物研究保育中心低海拔試驗站之台灣黑熊糞中性類固醇之濃度變化做一為期3年多觀察與研究。結果顯示，台灣黑熊為季節性發情的動物，繁殖季主要在3至6月間。公熊睪固酮濃度具有季節性變化，睪固酮於冬季開始有增加的趨勢，而在春季達到最高的濃度。有分娩記錄的台灣黑熊，雌二醇及孕酮濃度變化較無配種或有配種無分娩的母熊有規則性且孕酮呈現出階段性增加。懷孕期約為6-7.5個月，但因懷孕期差異頗大，推測可能包含有胚延遲埋植期。母熊於分娩前後會出現不飲、不食、不排泄及行動減緩等類似冬眠的行為。此外，於繁殖季睪固酮及雌二醇濃度高低並非唯一決定交配與否的因素，而圈養條件下台灣黑熊會因環境、氣候、年齡、健康、哺乳等因素，造成個體上頗大繁殖差異。本研究可推論出台灣黑熊於類似自然環境下的年活動模式，主要分為活動期及似冬眠期兩個模式且可能因氣候適宜及食物來源較不匱乏，因此不包括冬眠期。本研究的結果可作為台灣黑熊野外的調查及研究之參考，並為台灣生物多樣性的維護略盡綿薄。The present study utilized non-invasive enzyme-linked immunosorbent assays(ELISA) to measure the changes of fecal reproductive steroids in 6 Formosan black bears (Ursus thibetanus formosanus)at the Low Altitude Experimental Station of Endemic Species Research Institute. The results indicated Formosan black bears were seasonal breeder and the major breeding season was between March and June. Testosterone concentrations were fluctuated according to seasonal changes. The concentrations increased in late winter and reached to the highest peak in spring. Relatively regular patterns of estradiol and progesterone concentrations in pregnancy were observed in parturient females, and the gestation periods were about 6 to 7.5 months. Because the gestation periods were different, it might include a special reproductive phenomenon, delayed implantation of embryo. Moreover, female Formosan black bears have hibernated behaviors, such as, fasting, non-excretion and sluggish activity at about a period before and after parturition. In non-mated females, progesterone concentrations were irregular and the peaks were lower than the mated bears. Health condition and environmental factors influences caused different reproductive behaviors in each individual. Thus, testosterone and estradiol concentrations were not the only factor that had influenced on mating behavior. The annual pattern could be divided into an active and like-hibernate period. Because of well climate and abundant food, the annual pattern did not include hibernation. This study provides useful information for the wildlife research and management of the Formosan black bears. Furthermore, the present study could also contribute to the conservation of Taiwanese biodiversity.一、緒言 二、文獻探討 第一節 台灣黑熊簡介 第二節 熊科動物年活動週期繁殖模式 第三節 熊科動物繁殖行為 第四節 熊科動物繁殖生理 一、雄性熊科動物 (一) 睪丸解剖學與細胞學 (二) 精子生成 (三) 性類固醇生成酵素 (四) 公熊繁殖內分泌 二、雌性熊科動物 (一) 母熊繁殖器官解剖學與細胞學特徵 (二) 性類固醇生成酵素 (三) 特殊繁殖現象 (四) 母熊繁殖內分泌 第五節 性類固醇之研究與應用 一、類固醇的合成、生物效應及臨床應用 (一) 類固醇的合成 (二) 睪固酮的生物效應及臨床應用 (三) 動情素的生物效應及臨床應用 (四) 孕酮的生物效應及臨床應用 二、類固醇的代謝及分析 (一) 類固醇的代謝 (二) 類固醇的分析 三、糞材中性類固醇之研究與應用 三、雄性台灣黑熊糞中睪固酮分析 第一節 前言 第二節 材料與方法 一、實驗動物 二、糞材收集及萃取 三、酵素免疫分析法 (一) 試藥之製備 (二) 抗體及睪固酮-酵素聯結體之製備與濃度選擇 (三) 標準溶液之配置與標準曲線之建立 (四) 靈敏度、分析內與分析間變異係數 (五) 糞中睪固酮酵素免疫分析法之步驟 第三節 結果 第四節 討論 四、雌性台灣黑熊糞中雌二醇和孕酮的分析 第一節 前言 第二節 材料與方法 一、實驗動物 二、糞材收集及萃取 三、酵素免疫分析法 (一) 試藥之製備 (二) 抗體及類固醇-酵素聯結體之製備與濃度選擇 (三) 標準溶液之配置與標準曲線之建立 (四) 靈敏度、分析內與分析間變異係數 （五）糞中雌二醇和孕酮酵素免疫分析法之步驟 第三節 結果 第四節 討論 五、結

Resveratrol protects against diet-induced atherosclerosis by reducing low-density lipoprotein cholesterol and inhibiting inflammation in apolipoprotein E-deficient mice

Objective(s):Resveratrol (RES) is a polyphenol compound that has been shown a promising cardioprotective effect. However, some reports have yielded conflicting findings. Herein, we investigated the anti-atherosclerotic effects of RES in apolipoprotein E (apo E)-deficient mice on a high cholesterol diet. Materials and Methods: Firstly, atherosclerosis was induced by feeding a high cholesterol diet to apo E-deficient mice. Then, we examined its effects on weight control, and serum interleukin-6 (IL-6) levels and used histopathological methods to analyze morphology and inflammatory marker of atherosclerotic lesions in mice orally supplemented with high (25 mg/kg/day) and low (5 mg/kg/day) doses of RES for 8 weeks. Results: Mice with high dose of RES had reduced epididymal fat pads, and lower serum IL-6 levels compared with those of control mice. Moreover, RES in high doses also decreased the low-density lipoprotein cholesterol (LDL-C) levels and atherogenic index (LDL-C/HDL-C) in the mice. Dissection of high-dose RES-treated mice revealed a marked reduction in fat deposition, percentage of mice with atherosclerotic lesion, and intima/media ratio in the aortic areas.Theexpressions of macrophage-specific marker F4/80 and cardiovascular inflammatory marker NF-κB in atherosclerotic vessels were both diminished in the atherosclerotic vessels of high-dose RES-supplementated apo E-deficient mice. Conclusion: These results suggest that RES prevented the effects of a high cholesterol diet onthe rate of accretion in atherosclerosis progression by reducing the LDL-C levels and suppressing atherosclerotic inflammation. RES can therefore be valuable in the development of new anti-atherosclerotic agents

Implications of hydrogen uptake and transport for corrosion fatigue crack growth

SIGLEAvailable from British Library Document Supply Centre-DSC:DXN023899 / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Hematocrit and Plasma Chemistry Values in Adult Collared Scops Owls (Otus lettia) and Crested Serpent Eagles (Spilornis cheela hoya)

In this study, we report hematocrit and plasma chemistry values for adult captive collared scops owls (Otus lettia) and crested serpent eagles (Spilornis cheela hoya). In particular, we address the gender-specific differences within these values. We measured hematocrit (HCT) and plasma chemistry values for uric acid (UA), plasma urea nitrogen (BUN), total protein (TP), albumin (ALB), glucose (GLU), cholesterol (CHO), triglyceride (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), lactate dehydrogenase (LDH), alkaline phosphatase (ALP), total bilirubin (TBIL), creatine (CRE), creatine phosphokinase (CPK), amylase (AMY), calcium (CA), ionic phosphorous (IP) and sodium (NA), potassium (K) and chloride ions (CL) in 37 adult captive collared scops owls and 39 adult captive crested serpent eagles. Significant differences between the sexes were found for UA, GLU and CPK in the collared scope owls. UA and GLU concentrations were significantly higher (P<0.01 and P<0.05) among males than females, while the CPK concentration was significantly lower (P<0.05) in males. There were no significant differences in of all of the measured parameters between male and female eagles. These finding suggested that HCT and plasma chemistry values of raptors vary individually according to species and sex. Our results provide the 1st available reference data for ranges of plasma values in adult captive collared scops owls and crested serpent eagles, making them a potentially useful complementary diagnostic tool for veterinary care of individuals for both species in captivity

Isoproterenol exacerbates hyperglycemia and modulates chromium distribution in mice fed with a high fat diet

Isoproterenol (ISO), a nonselective β-adrenoceptor agonist for treating bradycardia and asthma, has been proposed to raise blood glucose level. Little is known regarding the relationship between ISO treatment, the induced chromium (Cr) redistribution, and changes in glucose metabolism. We aimed to characterize the effects of a single dose of ISO on glucose homeostasis and Cr level changes in an obesity mouse model

Fecal reproductive steroid profiles for monitoring reproductive patterns in female Formosan black bears (Ursus thibetanus formosanus)

Fecal sexual estradiol (E(2)) and progesterone (P(4)) analyses were conducted on three adult female Formosan black bears in order to establish non-invasive enzyme-linked immunosorbent assays (ELISA) for describing the endocrine profile in a simulated natural breeding environment. Moreover, we investigated whether the Formosan black bear living in subtropical habitats in Taiwan is a seasonal breeder with delayed embryo implantation, ovulation pattern, and maternal perinatal fasting. Our results indicate that mating behavior occurred both before and after the fecal E(2) peak of March June. Fecal P(4) concentrations initially increased after mating, then decreased to lower levels, and finally increased again, which is indicative of a delayed embryo-implantation. Fecal P(4) levels decreased postpartum. Peaks of fecal P(4) levels were also observed in unmated female bears housed with male bears without coitus: their annual fecal P(4) levels were higher from winter to spring, similar to the pregnant female bear: Interestingly, only pregnant female bears displayed a physiological state of fasting before and after parturition. These results suggest that Formosan black bears' breeding is seasonal and takes place from spring to early summer. Delayed implantation, maternal perinatal fasting and induced ovulation from male stimulation independent of coital stimulation alone are typical for the species