Adipogenic Toxicity Study of Obesogenic Drugs

致肥药物的脂肪毒性研究

基本信息

批准号：
8488448
负责人：
Yuanxiang Zhao
金额：
$ 10.17万
依托单位：
CALIFORNIA STATE POLY U POMONA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8488448
关键词：
Acute Address Adipocytes Adipose tissue Adverse effects Affect Amitriptyline Anti-Retroviral Agents Antidepressive Agents Antidiabetic Drugs Antiepileptic Agents Atazanavir Awareness Bone Marrow Carbamazepine Cardiovascular Diseases Caring Categories Cell Culture Techniques Cell Cycle Arrest Cell Maturation Cell Proliferation Cell model Cells Cellular biology Characteristics Chemicals Chronic Clinical Clozapine Development Diabetes Mellitus Diet Doxazosin Drug Prescriptions Educational process of instructing Endothelial Cells Enrollment Event Faculty Fatty Acids Fatty acid glycerol esters Fibroblasts Fostering Foundations Future Gene Expression Profile Gene Targeting Genes Glyburide Glycerol Goals Health Health Professional Homeostasis Human Human Development Hypertension In Vitro Individual Institution Intra-abdominal Knowledge Lead Learning Life Life Style Light Link Lipids Lipolysis Lopinavir MAP Kinase Signaling Pathways Measures Medical Mesenchymal Stem Cells Mesylates Metabolic Microarray Analysis Mind Minority Mitogen-Activated Protein Kinases Molecular Molecular Biology Nonesterified Fatty Acids Normal tissue morphology Obesity Osteocytes Paroxetine Patient Care Patients Pharmaceutical Preparations Pharmacologic Substance Physical activity Pioglitazone Play Process Productivity Proliferating Propranolol Public Health Publications Regenerative Medicine Regulation Research Risk Risperidone Role Sertraline Signal Transduction Solutions Stem Cell Research Stem cells Stimulus Students System Testing Thigh structure Tissues Toxic effect Toxicity Tests Triglycerides United States Valproic Acid Visceral Weight Gain Work adult stem cell atypical antipsychotic base bone cell career cell type drug market drug testing embryonic stem cell energy balance environmental chemical experience glucose uptake improved in vitro testing interest lipid biosynthesis macrophage molecular marker novel olanzapine osteogenic peripheral blood prevent prototype public health relevance response safety testing skills stem cell biology subcutaneous treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Obesity rate has been on the rise in the United States over the past decades. While life style change in diet and physical activities is recognized as the primary cause of obesity, there are other contributing factors as well. Many common drugs prescribed to millions of people each year have been clinically linked to significant weight gain as a result of undesired side effect (referred to as obesogenic effect), but the underlying pharmacological mechanisms are poorly understood. Medication-induced obesity could lead to other health risks including diabetes and cardiovascular diseases, as well as a risk of adverse effect from discontinuing the medication. The lack of understanding of how different medications can cause weight gain makes it difficult to prevent or counteract this side effect. To help address this knowledge gap, this study proposes to examine 14 drugs of known obesogenic effects for potential direct disruption of lipogenesis and lipolysis, the two opposing events in regulating adipose tissue homeostasis. The adipose tissue is composed of predominantly adipocytes (fat cells), in addition to preadipocytes (precursors of adipocytes), human mesenchymal stem cells (hMSCs) and a few other cell types including macrophages and endothelial cells. Accumulation of fat results from adipogenic differentiation of hMSCs, maturation of preadipocytes into adipocytes or continuous accumulation of fat in adipocytes, whereas loss of fat results from the breakdown of fat into glycerol and fatty acids in adipocytes. Weight gain could result from accumulation of fat or decrease in fat reduction. Specifically, the following 4 aims are proposed to examine the direct effect of selected obesogenic drugs on adipose tissue: Aim 1, determine how each drug singularly or in combination with other treatments could affect the cell fate determination of hMSCs to become fat cells or bone cells; Aim 2, examine how each drug singularly or in combination with other treatments could affect the differentiation of preadipocytes into adipocytes under either acute or chronic exposures. Two subtypes of preadipocytes from the same donor, intra-abdominal and subcutaneous, will be tested in order to assess potential differential response of cells from different fat depots; Aim 3, examine the potential effect of each drug on the accumulation and lipolytic rate of fat in adipocytes under acute or chronic exposures; And Aim 4, explore the molecular mechanisms underlying the identified in vitro obesogenic effect of drugs in the previous 3 aims. This proposed study would help to gain knowledge about the potential direct actions of known obesogenic drugs on adipose homeostasis and potentially shed new light on the molecular mechanisms underlying the regulation of adipose homeostasis. Knowledge obtained from this study will help clinical and public health professionals provide more informed care of their patients and develop treatment strategies for preventing drug associated weight gain. Furthermore, it will help establish prototypes of testing modules for predicting adipogenic toxicity of a wide range of existing drugs in the market, drugs in development, as well as environmental chemicals.

描述（由申请人提供）：在过去的几十年中，肥胖率一直在美国上升。尽管饮食和体育活动中的生活方式变化被认为是肥胖的主要原因，但还有其他促成因素。由于不希望的副作用（称为肥胖作用），每年为数百万人开处方的许多常见药物与大量体重增加有关，但是对基本的药理机制的了解很少。药物引起的肥胖症可能导致其他健康风险，包括糖尿病和心血管疾病，以及在停止药物中造成不利影响的风险。缺乏对不同药物如何导致体重增加的理解，因此难以预防或抵消这种副作用。为了帮助解决这一知识差距，本研究建议检查14种已知肥胖作用的药物，以潜在地直接破坏脂肪生成和脂解，这是调节脂肪组织稳态的两个相反事件。脂肪组织还由主要是脂肪细胞（脂肪细胞）组成，除了前脂肪细胞（脂肪细胞的前体），人间充质干细胞（HMSCS）以及其他一些细胞类型以及包括巨噬细胞和内皮细胞在内的其他细胞类型。脂肪的积累是由HMSC的脂肪生成分化，脂肪细胞成熟到脂肪细胞中的成熟或脂肪中脂肪的连续积累，而脂肪损失导致脂肪损失导致脂肪细胞中脂肪中的甘油和脂肪酸分解。体重增加可能是由于脂肪的积累或减少脂肪减少而导致的。具体而言，提出了以下4种目的，以检查选定的肥胖药物对脂肪组织的直接作用：AIM 1，确定每种药物如何单一或与其他处理结合使用可能影响HMSC的细胞命运确定成为脂肪细胞或骨细胞的细胞命运。 AIM 2，检查每种药物在急性或慢性暴露下如何奇异地或与其他治疗结合可能影响脂肪细胞为脂肪细胞的分化。将测试来自同一供体腹腔内和皮下的两种亚型，以评估不同脂肪库中细胞的潜在差异反应。 AIM 3，检查每种药物对急性或慢性暴露下脂肪细胞中脂肪的积累和脂肪速率的潜在影响； AIM 4，探讨了前3个目标中药物体外性肥胖作用的分子机制。这项拟议的研究将有助于了解已知的肥胖药物对脂肪稳态的潜在直接作用的知识，并有可能对调节脂肪稳态调节的分子机制有了新的启示。从这项研究中获得的知识将有助于临床和公共卫生专业人员提供对患者的更明智的护理，并制定治疗策略，以防止药物相关的体重增加。此外，它将有助于建立测试模块的原型，以预测市场中广泛的现有药物的成脂毒性，开发中的药物以及环境化学品。