The Inhibitory Effect of Antipsychitics on the Mechanisms of Adiponectin Gene Expression and Secretion

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Project title

Code/計畫編號

NSC98-2320-B019-002

Translated Name/計畫中文名

抗精神病藥物抑制Adiponectin基因表現及分泌機制之探討

Project Coordinator/計畫主持人

Shiow-Yi Chen

Funding Organization/主管機關

National Science and Technology Council

Department/Unit

Department of Bioscience and Biotechnology

Website

https://www.grb.gov.tw/search/planDetail?id=1907977

Year

2009

Start date/計畫起

01-08-2009

Expected Completion/計畫迄

01-07-2010

Bugetid/研究經費

600千元

ResearchField/研究領域

基礎醫學
生物技術(醫)

"現今臨床使用的第二代抗精神病藥物(又稱非典型抗精神病藥物)易造成體重增加，使精神病患易罹患糖尿病、心血管疾病及其它的併發症。目前對於抗精神病藥物引發體重增加機制並不清楚。由於肥胖者血清中 adiponectin 濃度較瘦者來得低，且研究顯示血清中低adiponectin 易造成胰島素阻抗性及增加冠狀動脈硬化的罹患率。然而adiponectin 與抗精神病藥物之相關研究非常缺乏，為了解是否adiponectin 與抗精神病藥物引發體重增加是否具相關性，本實驗室先前在臨床上針對體重過重之精神病患換成低體重增加量的抗精神病藥物amisulpride 一年間，偵測病患血清中 adiponectin 濃度，結果adiponectin 濃度增加與體重及腰圍的變化呈現負相關，即病患換藥後體重減輕，血清中adiponectin 增加。在基礎研究部分，我們證實易造成體重增加的抗精神病藥物可直接抑制脂肪細胞的 adiponectin 基因表現及分泌，而抗精神病藥物amisulpride 並不會抑制脂肪細胞分泌adiponectin。此外,我們初步結果也證實，易造成體重增加的抗精神病藥物可促進前脂肪細胞之分化造成脂質堆積及抑制脂肪細胞 adiponectin 基因表現，其機制可能是經由adipoR2，adipoR2 途徑主要涉及壓力及發炎反應，因而在此假設(1) 抗精神病藥物改變脂肪細胞代謝能力，抑制adiponectin 基因表現及分泌；(2) 抗精神病藥物透過壓力及發炎反應抑制adiponectin 基因表現及分泌。目前並無文獻探討抗精神病藥物對adiponectin 基因表現與分泌的調控之相關研究，本計劃擬從二方面先探討抗精神病藥物抑制adiponectin 基因表現與分泌之機制； (1)抗精神病藥物是否透過影響脂肪細胞老化、粒線體生成及其功能，抑制adiponectin 的基因表現和分泌；(2) 抗精神病藥物是否透過缺氧(hypoxia) 、過氧壓力(oxidative stress) 、內質網壓力 (endoplasmic reticulum stress)及發炎反應(inflammation)而抑制adiponectin 的基因表現和分泌。由於adiponectin 具抗糖尿病、冠狀動脈硬化及發炎反應等特性，此計劃有助於了解抗精神病藥物對adiponectin 基因表現與分泌之抑制之相關機制，作為未來研究臨床精神用藥及藥物開發之參考。" "Second-generation antipsychotics (also called atypical antipsychotics) have the vulnerability of the side effect of weight gain. Patients taking these medicines raise the risk of getting diabetes, cardiovascular and other co-morbid diseases. Adiponectin levels are lower in obese than lean subjects Several studies demonstrated hypoadiponectin can induce insulin resistance and increase risk for atherosclerotic diseases. However, the related researches between antipsychotics and adiponectin remains poorly characterized. To study whether adiponectin is associated with antipsychotic-induced weight gain, we recruited chronic psychotic inpatients with overweight and evaluate the change in adiponectin after switching to low weight gain antipsychotics from taking other antisychotics for one year. A negative correlation was found between adiponectin, and body weight and waist circumference, respectively. Our preliminary results demonstrated that antipsychotics with high weight gain effect can directly inhibit adiponectin gene expression and secretion, but not amisulpride. Besides, we also demonstrated that antipsychoyics promoted adipocyte differentiation, fat accumulation and inhibited adiponectin gene expression which is involved in stress and inflammation via adipoR2 in adipocyte. Based on our preliminary findings, we hypothesize that (1) antipychotics inhibit adiponectin gene expression and secretion through change of capacity of adipocyte metabolism ; (2) antipychotics inhibit adiponectin gene expression and secretion through stress and inflammation. At present, no paper discusses the effect of antipsychotics on regulation of adiponectin gene expression and secretion. Regulation of adiponectin gene expression and secretion is very complex. Based on present data, antipsychotics promote fat accumulation and adiponectin gene regulation involved in stress and inflammation.To explore the inhibitory effect of antipsychotics on adiponectin gene expression and secretion, we plan he following goals in the next two years below: ．Elucidate whether antipychotics inhibit adiponectin gene expression and secretion through adipocyte aging and mitochondrial biogenesis and mitochondrial dysfunction. ．Elucidate whether antipychotics inhibit adiponectin gene expression and secretion through hypoxia, oxidative stress, endoplasmic reticulum stress and inflammation. Because adiponectin owns antidiabetic, antiatherogenic and anti-inflammatory properties, we believe these approaches outlined above may help understand the inhibitory effect of antipsychotics on adipocyte and adiponectin gene expression and secretion of adipocytes. It may have implications for further researches in clinical practice of antipsychotic medications and antipsychotic drug development."

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The Inhibitory Effect of Antipsychitics on the Mechanisms of Adiponectin Gene Expression and Secretion

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