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

Effects of Growth Hormone Treatment on Height, Weight, and Obesity in Taiwanese Patients with Prader-Willi Syndrome

BackgroundInformation regarding the efficacy of growth hormone (GH) therapy in Asian Prader-Willi syndrome (PWS) patients is lacking. We report our experience with GH treatment in children with PWS in Taiwan.MethodsForty-six PWS patients (27 males, 19 females; age range, 1 year 4 months to 13 years 7 months) who received and/or who are currently receiving GH treatment (0.1 IU/kg/day subcutaneously) for a period from 1 year to 3 years were retro-spectively analyzed. We evaluated height, weight, body mass index (BMI) and Rohrer index, before and after GH treatment.ResultsAfter patients had received GH for 1, 2 and 3 years, a significant improvement in mean height standard deviation score (SDS) was noted from −1.24 to −0.31 (p <0.01), 0.00 (p <0.001) and −0.26 (p <0.001), respectively. Mean BMI SDS decreased significantly from 1.93 to 1.13 (p <0.05) after 1 year of treatment; however, no significant changes were observed afterward. Mean Rohrer index decreased significantly, from 224.2 to 186.6 (p <0.001), 178.9 (p <0.001) and 169.3 (p <0.001). No significant gender or genotype pattern differences were noted among the 4 parameters examined.ConclusionThis 3-year, retrospective study indicates that PWS patients benefit from GH therapy in height increase and improved body composition

Mutations in KEOPS-Complex Genes Cause Nephrotic Syndrome with Primary Microcephaly

Galloway-Mowat syndrome (GAMOS) is an autosomal-recessive disease characterized by the combination of early-onset nephrotic syndrome (SRNS) and microcephaly with brain anomalies. Here we identified recessive mutations in OSGEP, TP53RK, TPRKB, and LAGE3, genes encoding the four subunits of the KEOPS complex, in 37 individuals from 32 families with GAMOS. CRISPR-Cas9 knockout in zebrafish and mice recapitulated the human phenotype of primary microcephaly and resulted in early lethality. Knockdown of OSGEP, TP53RK, or TPRKB inhibited cell proliferation, which human mutations did not rescue. Furthermore, knockdown of these genes impaired protein translation, caused endoplasmic reticulum stress, activated DNA-damage-response signaling, and ultimately induced apoptosis. Knockdown of OSGEP or TP53RK induced defects in the actin cytoskeleton and decreased the migration rate of human podocytes, an established intermediate phenotype of SRNS. We thus identified four new monogenic causes of GAMOS, describe a link between KEOPS function and human disease, and delineate potential pathogenic mechanisms

The Study of Olanzapine Combines Exercise on Metabolic Disturbances in C57BL/6JNarl Mice

Olanzapine， 為一第二代抗精神分裂症藥物，主要作用在拮抗腦中的血清素、組織胺與多巴胺接受器。此藥物雖改善了患者的精神狀態但卻會產生高血糖、糖尿病、肥胖的代謝異常的副作用，提高服藥者因心血管疾病而死亡的死亡率。已知運動具有降低體重改善肥胖並且增加胰島素敏感性等優點，因此本研究以olanzapine (6 mg/kg BW)誘導C57BL/6JNarl小鼠代謝異常並合併電動跑步機方式的運動訓練來看olanzapine對該品系小鼠造成的變化以及運動對olanzapine導致小鼠代謝異常的影響。在本研究中，給予小鼠olanzapine五週後，發現該組小鼠相較對照組有顯著體重增加、食慾增加、禁食血糖升高、serum insulin增加、serum leptin增加與肝臟三酸甘油脂增加的現象；而合併運動訓練可降低小鼠禁食血糖、serum insulin與HOMA-IR等改善胰島素敏感性的現象，但是對於升高的serum leptin、肝臟三酸甘油脂與食慾未發現有抑制效果。在脂肪細胞方面，給予olanzapine的小鼠相較於對照組有較多的腹腔脂肪、皮下脂肪與較大的腹腔脂肪細胞，且對於腹腔脂肪中hormone sensitive lipase (HSL)有減少表現的趨勢，而合併運動則有助於減少腹腔脂肪的堆積。關於能量代謝方面，給予olanzapine的小鼠相較對照組在負責調節體溫的棕色脂肪組織有顯著增加，HSL表現量亦顯著增加，而合併運動對於這方面未見有影響。Leptin為一由脂肪細胞所分泌的荷爾蒙，負責調節食慾、體溫與能量代謝，因此，根據本研究結果推測olanzapine所造成的小鼠代謝異常現象與leptin的調節有關連，而合併運動雖能改善胰島素敏感性與高血糖，但無法改善因olz而升高的肝臟三酸甘油脂代謝與leptin resistance。Olanzapine (olz) is a second generation antipsychotic drug which works on serotonin receptors and dopamine receptors in the brain. Olz is greatly used because it possess advantages over old agents (first generation antipsychotics) in terms of reduced adverse effects like extrapyramidal symptoms. However, olanzapine also induces a marked side effect including weight gain, raising blood glucose level and reducing insulin sensitivity. These have been indicated to be associated with metabolic syndrome. On the other hand, exercise is known for its benefits in weight management. It also lowers blood glucose and improves insulin sensitivity. C57BL/6JNarl female mice have been selected in this study to investigate the metabolic disturbance that induced by olz. Moreover, whether exercise may compensate the side-effect that induces by olz was also studied here. Our results show that olz can induce an significantly increase in weight gain, food intake, accumulation of visceral and subcutaneous adipose tissue, blood glucose level, serum insulin level, serum leptin and liver triglyceride in model mice. Exercise is observed to be effective in reducing the effects of olz on blood glucose, serum insulin and improve HOMA-IR. Exercise also reduces accumulation of adipose tissue, but fails in lowering serum leptin and liver triglyceride. The expression of hormone sensitive lipase (HSL) is lower in visceral fat of mice treated by olz. We also observed that mice given olanzapine led to reduce their body temperature but increase in HSL expression in brown adipose tissue. Our data suggests that C57BL/6JNarl mice treated with olz reduces energy expenditure and increases food intake which similar to the effects of leptin resistance and the combination of exercise seems to be helpful in the glucose metabolism but show no effects in the lipid metabolism.目錄 中文摘要..i Abstract..ii 目次......iii 表次......iv 圖次......v 第一章 緒言....1 第二章 文獻探討....3 第一節 精神分裂症簡介....3 第二節 精神分裂症用藥....3 1. 簡介...3 2. Olanzapine...4 第三節 代謝症候群....5 第四節 胰島素阻抗....5 第五節 Leptin.......6 1. Leptin & Leptin resistance...6 2. Leptin與長期運動....6 3. Leptin與憂鬱症......7 第六節 運動、血糖與胰島素..7 第七節 體溫調節作用........7 第八節 下視丘-腦下垂體-腎上腺(Hypothalamic– pituitary–adrenal (HPA)axis)......8 第三章 材料與方法....11 第一節 實驗動物......11 第二節 實驗設計及方法.12 第三節 血清生化數值分析..13 第四節 組織切片製備及細胞大小計算..13 第五節 肝臟與肌肉三酸甘油脂之分析法..13 第六節 HOMA(homeostasis model assessment)-IR(insulin resistance)之分析方法...13 第七節 蛋白質分析.....14 第八節 統計分析.......16 第四章 結果...........17 第五章 討論...........20 第六章 結論...........22 參考文獻....36 附錄.....4