Adipogenic Toxicity Study of Obesogenic Drugs

致肥药物的脂肪毒性研究

• 批准号: 8098220
• 负责人: Yuanxiang Zhao
• 金额: $ 10.54万
• 依托单位: CALIFORNIA STATE POLY U POMONA
• 依托单位国家: 美国
• 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/8098220
• 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

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. PUBLIC HEALTH RELEVANCE: This project is aimed to provide better understanding of the mechanisms underlying some common cases of medication-induced weight gain as an undesired side effect. Findings from this proposed study will provide useful information to the clinical and public health professionals for improved care of patients who rely on these medications, enhance our understanding of the regulation of fat tissue homeostasis, and help establish in vitro testing modules for predicting potential toxicity effect of a wide range of existing and future drugs as well as environmental chemicals.

描述(由申请者提供)：在过去的几十年里，美国的肥胖率一直在上升。虽然饮食和体育活动中生活方式的改变被认为是肥胖的主要原因，但也有其他促成因素。每年给数百万人开的许多常见药物在临床上都与不良副作用(称为肥胖效应)导致的显著体重增加有关，但其潜在的药理机制尚不清楚。药物引起的肥胖可能会导致其他健康风险，包括糖尿病和心血管疾病，以及停止服药产生不良影响的风险。由于缺乏对不同药物如何导致体重增加的了解，因此很难预防或抵消这种副作用。为了帮助解决这一认识差距，这项研究建议检查14种已知的致肥胖作用的药物，以潜在地直接破坏脂肪生成和脂肪分解，这是调节脂肪组织动态平衡的两个相反的事件。脂肪组织主要由脂肪细胞(脂肪细胞)组成，此外还有前脂肪细胞(脂肪细胞的前体)、人间充质干细胞(HMSCs)和一些其他类型的细胞，包括巨噬细胞和内皮细胞。脂肪的蓄积源于hMSCs的成脂分化、前体脂肪细胞向脂肪细胞的成熟或脂肪细胞内脂肪的持续蓄积，而脂肪的丢失则源于脂肪细胞内脂肪分解为甘油和脂肪酸。体重增加可能是由于脂肪堆积或脂肪减少所致。具体地说，提出了以下4个目的，以考察选定的致肥药物对脂肪组织的直接影响：目的1，确定每种药物单独或与其他处理组合如何影响hMSCs成为脂肪细胞或骨细胞的细胞命运决定；目标2，研究每种药物单独或与其他处理组合如何影响急性或慢性暴露下前脂肪细胞向脂肪细胞的分化。将测试来自同一供体的两种亚型的前脂肪细胞，即腹内和皮下脂肪细胞，以评估来自不同脂肪库的细胞的潜在差异反应；目的3，检测每种药物在急性或慢性暴露下对脂肪细胞脂肪蓄积和脂肪分解速率的潜在影响；以及目的4，探讨前三个目的中已确定的药物体外促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促肥胖药物对脂肪稳态的潜在直接作用，并可能为调节脂肪稳态的分子机制提供新的线索。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为他们的患者提供更知情的护理，并制定防止与药物相关的体重增加的治疗策略。此外，它将有助于建立测试模块的原型，用于预测市场上各种现有药物、正在开发的药物以及环境化学品的成脂毒性。 与公共卫生相关：该项目旨在更好地了解一些常见的药物引起的体重增加作为不良副作用的机制。这项拟议研究的结果将为临床和公共卫生专业人员提供有用的信息，以改善对依赖这些药物的患者的护理，增进我们对脂肪组织动态平衡调节的了解，并有助于建立体外测试模块，用于预测各种现有和未来药物以及环境化学品的潜在毒性效应。