Adipogenic Toxicity Study of Obesogenic Drugs

描述（由申请人提供）：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的生活方式改变被认为是肥胖的主要原因，但也有其他因素。每年向数百万人开出的许多常见药物在临床上与由于不期望的副作用（称为致肥胖作用）而导致的显著体重增加有关，但对潜在的药理学机制知之甚少。药物引起的肥胖可能导致其他健康风险，包括糖尿病和心血管疾病，以及停止药物治疗的不良影响。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。为了帮助解决这一知识差距，本研究提出了检查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解，这两个相反的事件在调节脂肪组织的稳态。脂肪组织主要由脂肪细胞（脂肪细胞）、前脂肪细胞（脂肪细胞的前体）、人间充质干细胞（hMSC）和包括巨噬细胞和内皮细胞在内的少数其他细胞类型组成。脂肪的积累由hMSC的成脂分化、前脂肪细胞成熟为脂肪细胞或脂肪在脂肪细胞中的连续积累引起，而脂肪的损失由脂肪在脂肪细胞中分解为甘油和脂肪酸引起。体重增加可能是由于脂肪积累或减少脂肪减少。具体而言，提出了以下4个目的来检查所选致肥胖药物对脂肪组织的直接作用：目的1，确定每种药物单独或与其他治疗组合如何影响hMSC成为脂肪细胞或骨细胞的细胞命运决定;目标二，研究每种药物单独或与其他治疗组合如何影响前脂肪细胞在急性或急性下向脂肪细胞的分化，或慢性暴露。将测试来自同一供体的两种亚型的前脂肪细胞，腹腔内和皮下，以评估来自不同脂肪库的细胞的潜在差异反应;目的3，检查在急性或慢性暴露下每种药物对脂肪细胞中脂肪蓄积和脂解速率的潜在影响;目的4，探讨前三个目的中药物致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致肥胖药物对脂肪稳态的潜在直接作用，并可能揭示脂肪稳态调节的分子机制。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明智的护理，并制定预防药物相关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，用于预测市场上现有药物、开发中药物以及环境化学品的脂肪形成毒性。 公共卫生相关性：该项目旨在更好地了解药物引起的体重增加作为不良副作用的一些常见情况下的机制。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，以改善依赖这些药物的患者的护理，增强我们对脂肪组织稳态调节的理解，并帮助建立体外测试模块，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作用。

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.