Resistance to excessive bodyweight gain in risperidone-injected rats.

IF 2.4 4区 医学 Q3 PHARMACOLOGY & PHARMACY
Miyuki Ota, Keiji Mori, Akira Nakashima, Yoko S Kaneko, Hisahide Takahashi, Akira Ota
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引用次数: 21

Abstract

1. The present study was carried out to explain the resistance of rats injected subcutaneously with risperidone, the atypical antipsychotic drug, for 21 consecutive days at 0.1 mg/kg per day (a dose equivalent to the one used for patients) to result in an excessive bodyweight despite the increase in diet-uptake in rats against risperidone-induced decrease in body temperature. 2. Rectal temperature measurements were made in 8-week-old male Sprague-Dawley rats maintained under standard laboratory conditions using a 12 h daylight cycle. A s.c. injection of risperidone (0.05 mg/kg) produced hypothermia in rats, which was observed during the daily injection for 21 consecutive days. 3. Sera, white and brown adipose tissues, skeletal muscle and liver were extracted from 8-week-old male Sprague-Dawley rats injected subcutaneously with risperidone (0.01 or 0.1 mg/kg per day) or a vehicle for 21 consecutive days. Serum levels of lipids, ketones and thyroid hormone were measured. The mRNA expression levels in these tissues and organs of the genes encoding the substances involved in heat production and/or lipid metabolism were investigated by using quantitative real-time polymerase chain reaction amplification. 4. Serum nonesterified fatty acid levels in risperidone 0.1 mg/kg per day s.c. injected rats were significantly lower than those in vehicle-injected ones. Serum beta-hydroxybutyrate levels in risperidone-injected rats tended to decrease compared with those in vehicle-injected ones. The serum level of neither triiodothyronine nor thyroxine was affected by risperidone s.c. injection at the doses examined, although their values were within normal limits. 5. Risperidone injection (0.1 mg/kg per day) for 21 consecutive days upregulated mRNA expressions in white adipose tissue of uncoupling protein 3 which dissipates energy as heat; peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1alpha which activates mitochondrial biogenesis to expand the oxidative machinery; and PPARalpha which is necessary for the fat-depletion of adipocytes for thermogenesis. The mRNA of lipogenic enzymes (acetyl-CoA carboxylase alpha, fatty-acid synthase and glycerol-3-phosphate acyltransferase), hormone sensitive lipase and beta1-adrenoceptor were also enhanced in white adipose tissue by the injection of 0.1 mg/kg per day risperidone. 6. These findings suggest that the materials for heat generation in white adipose tissue would be readily supplied, which in turn would reduce a storage of lipids in white adipose tissue resulting in the lower rate of bodyweight gain of rats.

利培酮注射大鼠对体重过度增加的抵抗力。
1. 本研究的目的是解释大鼠连续21天皮下注射非典型抗精神病药物利培酮(每天0.1 mg/kg)(剂量相当于患者使用的剂量),尽管大鼠饮食摄取增加,但对利培酮引起的体温下降却导致体重过重的原因。2. 在标准实验室条件下,用12小时的日光周期测量8周龄雄性sd大鼠的直肠温度。连续21天每日注射利培酮0.05 mg/kg,观察大鼠体温过低现象。3.取8周龄雄性Sprague-Dawley大鼠血清、白色和棕色脂肪组织、骨骼肌和肝脏,分别皮下注射利培酮(0.01或0.1 mg/kg / d)或载药,连续21 d。测定血脂、酮类及甲状腺激素水平。利用实时定量聚合酶链式反应扩增技术,研究了这些组织和器官中编码产热和/或脂质代谢物质的基因的mRNA表达水平。4. 0.1 mg/kg / d s.c.注射利培酮组大鼠血清非酯化脂肪酸水平显著低于车用大鼠。利培酮注射组大鼠血清β -羟基丁酸水平较车体注射组有降低的趋势。血清三碘甲状腺原氨酸和甲状腺素均未受利培酮注射剂量的影响,但均在正常范围内。5. 利培酮(0.1 mg/kg / d)连续21 d上调白色脂肪组织解偶联蛋白3 mRNA的表达,解偶联蛋白3以热量散失能量;过氧化物酶体增殖体激活受体(PPAR) γ辅激活因子1 α,激活线粒体生物发生,扩大氧化机制;以及ppar,这是脂肪细胞在产热过程中消耗脂肪所必需的。每天注射0.1 mg/kg利培酮可显著提高白色脂肪组织中脂肪生成酶(乙酰辅酶a羧化酶、脂肪酸合成酶和甘油-3-磷酸酰基转移酶)、激素敏感脂肪酶和β -肾上腺素能受体mRNA的表达。6. 这些发现表明,白色脂肪组织中产生热量的物质很容易供应,这反过来又会减少白色脂肪组织中脂质的储存,从而降低大鼠的体重增加率。
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来源期刊
Clinical and Experimental Pharmacology and Physiology
Clinical and Experimental Pharmacology and Physiology PHARMACOLOGY & PHARMACY-PHYSIOLOGY
自引率
0.00%
发文量
128
期刊介绍: Clinical and Experimental Pharmacology and Physiology is an international journal founded in 1974 by Mike Rand, Austin Doyle, John Coghlan and Paul Korner. Our focus is new frontiers in physiology and pharmacology, emphasizing the translation of basic research to clinical practice. We publish original articles, invited reviews and our exciting, cutting-edge Frontiers-in-Research series’.
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