| Background:Schizophrenia is mainly treated with drugs,among which the atypical antipsychotics drugs?AAPDs?represented by olanzapine?Olan?are most widely used in clinical,but a series of side effects gradually emerge along with the drug efficacy.Antipsychotics drugs induced weight gain for a long period of time,and more and more people pay attention to it,but the specific mechanism is unknown.Energy balance is an important factor in maintaining body weight,the imbalance between energy intake and output will lead to changes in body weight.Obesity can be considered as the result of high intake and low energy consumption.As a pathway of energy expenditure,thermogenesis may be one of the causes of Antipsychotics drugs induced weight gain,in which the brown adipose tissue?BAT?thermogenesis mediated by?3-adrenergic receptors is the main pathway.BAT exists in human and mammalian and consumes energy through the thermogenesis of Uncoupling Proteins?UCP?on the mitochondrial inner membrane.UCP1 is a thermogenesis marker protein specifically expressed in BAT,Peroxisome proliferatoractivated-activated receptor gamma?PPAR-??,PPAR?coactivator-1??PGC-1??,and PRD1-BF1-RIZ1 homologous domain containing16?PRDM16?are also involved in the thermogenesis of BAT.At present,some studies have shown that AAPDs can affect the thermogenesis of BAT,but the specific mechanism of how AAPDs affects the thermogenesis of BAT leading to weight gain is unclear.Epigenetic regulation,such as histone modification,plays a key role in adipogenesis and may be associated with weight gain,providing new insights into the metabolic side effects of antipsychotics.Objective:Dynamic observation of clinical patients taking Olan was carried out to determine the influence of Olan on the expression of UCP1 in patients.The correlation between UCP1 and clinical metabolic indexes was further analyzed to determine the role of thermogenic marker protein UCP1 in metabolic side effects mediated by Olan.Based on this,the?3-adrenergic receptor-agonist CL-316243 was used as a positive control to investigate the effects of?3-adrenergic receptor mediated thermogenic in BAT on Antipsychotics drugs induced weight gain in C57BL/6 mice,and the effects of histone modification in epigenetic modification on thermogenic in BAT was also preliminarily explored,which has important practical significance for guiding the rational use of AAPDs.Methods:1.A total of 49 schizophrenic patients in the sixth people's hospital of nanchong city,Sichuan province were selected to meet the research.The age,gender and other basic informations of the patients were recorded,and the clinical indicators of the patients were measured regularly,including:PANSS,MMSE,body weight,waist and hip circumference,blood glucose and lipid.The expression of UCP1 was determined by enzyme-linked immunosorbent assay?ELISA?.Pearson correlation analysis method was used to analyze the correlation between UCP1 and clinical indicators.2.A total of 48 C57BL/6 mice from 18 to 20 g were selected and divided into four groups:Control,Olan?3 mg/kg,i.g?,CL-316243?0.1 mg/kg,i.p?,and Olan 3 mg/kg,i.g+CL-316243,0.1 mg/kg,i.p.Twelve mice in each group were continuously treated with the drug respectively for four weeks,and their body weight,food and water intake were measured every other day.The changes in body temperature of mice were monitored by thermal imager and the changes in blood glucose and lipid content in the plasma of mice were measured every week.The glucose tolerance of mice was measured by IGTT before the end of administration.Finally,liver,white fat tissue?WAT?and BAT of mice were collected.The changes of fat droplets in each tissue of mice were observed by Sudan?staining,and the morphological changes of tissues were observed by HE staining.The expression of UCP1,PPAR-?,PGC1?and PRDM16 in BAT and the expression of AC-H3,AC-H4,TH3 and JMJD2B in total protein were detected by Western Blot.The expression of UCP1 was further verified by immunohistochemical analysis,and the expression of corresponding thermogenesis gene was determined by qPCR.Results:1.Effects of Olan on the clinical efficacy of patientsPANSS scores of patients were significantly decreased after one month treatment?P<0.001?,and MMSE scores were significantly increased after two months?P=0.0041?,indicating that Olan had a good clinical efficacy.2.Effects of Olan on body weight of patientsPatients,who taking Olan for two months,were observed on average weight gain of about 3.625 kg.BMI showed increasing trend in the process of the medicine,and it increased significantly after two months therapy?P=0.0160?.Waist circumference?P=0.0190?significantly increased after one month therapy,and the increase of the hip circumference?P>0.05?does not have significant.WHR was also significantly increased?P<0.01?,and patients showed central obesity.3.Effects of Olan on blood glucose and lipid of patientsAfter taking Olan for one month,patients showed abnormalities in triglyceride?TG?and high-density lipoprotein cholesterol?HDL-C?firstly.Compared with baseline,TG was significantly increased?P=0.0427?and was above the standard level,HDL-C was decreased significantly?P=0.0492?.In addition,total cholesterol?TC??P=0.0482?increased significantly after two months therapy,while fasting glucose?FPG?increased no significantly.4.Effect of Olan on UCP1 expression in serum of patients and its correlation analysisThe expression of UCP1 in serum of patients was significantly decreased?P=0.0279?after Olan treatment,and it was significantly negatively correlated with BMI,TG,TC?P<0.05?,positively correlated with HDL-C?r=0.343,P=0.016?,and was not significantly correlated with WHR,FPG and LDL-C?P>0.05?.5.Effects of Olan on body weight and food intake in miceFour weeks after Olan treatment,the body weight increment?P=0.0329?was significantly increased,while CL-316243 significantly reduced the cumulative body weight increment?P<0.05?increased by Olan.Olan had no significant effect on food and water intake as well as the weight of WAT and liver.But,after Olan treatment,there was significant lipid accumulation in the liver,and the lipid accumulation was relieved after CL-316243 administration.BAT showed a tendency to transform into WAT,and the cell volume and intercellular space became larger.WAT increased and became denser.6.Effects of Olan on glycolipid metabolism in miceAfter four weeks of Olan treatment,levels of TG?P=0.0026?and NEFA?P=0.021?were significantly increased,while HDL-C was significantly decreased?P=0.0283?.The CL-316243 reversed the decrease in TG?P=0.0016?.During the whole IGTT process,the glucose level of the Olan group was higher than that of the control group.Long-term treatment with Olan significantly increased the AUC of IGTT?P=0.0372?,which was reversed by CL-316243?P=0.0004?.7.Effects of Olan on thermogenesis in miceDuring the whole administration process,Olan treated mice showed a significant decrease in scapular temperature?P<0.05?,while CL-316243 significantly increased the body temperature?P<0.05?,and also reversed the low temperature caused by Olan.8.Effects of Olan on thermogenesis-related proteins and genes in miceBoth WB and immunohistochemical results showed that Olan significantly reduced the expression of UCP1 especially at low temperature.And the expression of UCP1 in CL-316243 group was significantly increased,and CL-316243 also reversed the Olan induced reduction of UCP1?P<0.01?.As for the thermogenesis cofactors,Olan only significantly decreased the expression of PGC-1??P=0.044?and PRDM16?P=0.0001?at low temperature.In addition,Olan significantly reduced the gene expression of Ucp1?P=0.0003?,Pgc-1??P=0.036?,and Prdm16?P=0.023?in mice treated at low temperature,and the reduction of Ucp1 was reversed by CL-316243?P=0.0001?.Expression of transcriptional regulation factor Ppar-??P=0.005?was significantly increased by Olan.9.Effects of Olan on acetylation or methylation of total protein in miceAfter Olan treatment,the levels of AC-H3?P=0.0012?,AC-H4?P=0.0001?and TH3?P=0.0434?in total BAT protein were significantly increased,while the levels of JMJD2B were decreased no significant.After CL-316243 administration,the increases in AC-H3?P=0.001?and AC-H4?P=0.0009?were reversed,while the effects on TH3,JMJD2B?P>0.05?were no significant.Conclusion:Our results showed that Olan,with its good efficacy,would lead to weight gain and associated with the risk of abnormal glucose and lipid metabolism.The expression of UCP1 in serum of patients was significantly decreased after taking medicine,and it was significantly correlated with BMI,TG,TC and HDL-C,suggesting that UCP1 may participate in metabolic side effects caused by Olan.In order to further explore the relationship between UCP1 and the abnormal energy metabolism caused by AAPDs,we conducted a basic study in C57BL/6 mice using?3-adrenergic receptor agonist CL-316243 as a positive control.The results showed that Olan mediated weight gain is possible that the expression of thermogenesis genes is regulated by affecting the histone modification of transcriptional regulators,thereby affecting the non-thriller thermogenesis in BAT mediated by?3-adrenergic receptors,resulting in abnormal energy metabolism and eventually lead to side effects such as weight gain. |
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