RESISTANCE TO EXCESSIVE BODYWEIGHT GAIN IN RISPERIDONE-INJECTED RATS
Authors: Ota, Miyuki1; Mori, Keiji2; Nakashima, Akira2; Kaneko, Yoko S2; Takahashi, Hisahide3; Ota, Akira2
Source: Clinical and Experimental Pharmacology and Physiology, Volume 32, Number 4, April 2005 , pp. 279-287(9)
Publisher: Blackwell Publishing
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Abstract:
SUMMARY 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
-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) 
coactivator 1
which activates mitochondrial biogenesis to expand the oxidative machinery; and PPAR which is necessary for the fat-depletion of adipocytes for thermogenesis. The mRNA of lipogenic enzymes (acetyl-CoA carboxylase , fatty-acid synthase and glycerol-3-phosphate acyltransferase), hormone sensitive lipase and 1-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.
Keywords:
bodyweight;
PGC-1;
peroxisome proliferator-activated receptor;
risperidone;
thermogenesis;
uncoupling protein 3;
white adipose tissue
Document Type: Research article
DOI: 10.1111/j.1440-1681.2005.04184.x
Affiliations: 1: Department of Neuropsychiatry, Tosei General Hospital, Seto, 2: Department of Physiology, Fujita Health University School of Medicine, Toyoake, and 3: Education and Research Center of Animal Models for Human Diseases, Fujita Health University Institute for Comprehensive Medical Science, Toyoake, Japan
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