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。每年数以百万计的人服用的许多常见药物在临床上都与体重显著增加有关，因为这些药物会产生意想不到的副作用（称为致肥效应），但其潜在的药理学机制尚不清楚。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，以及停药后产生不良反应的风险。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。为了帮助解决这一知识差距，本研究建议检查14种已知致肥作用的药物，以潜在地直接破坏脂肪生成和脂肪分解，这是调节脂肪组织稳态的两个相反事件。脂肪组织主要由脂肪细胞（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）和其他一些细胞类型，包括巨噬细胞和内皮细胞。脂肪的积累是由hMSCs的成脂分化、前脂肪细胞成熟为脂肪细胞或脂肪细胞中脂肪的持续积累引起的，而脂肪的损失是由脂肪细胞中脂肪分解为甘油和脂肪酸引起的。体重增加可能是由于脂肪的积累或脂肪减少的减少。具体来说，我们提出以下4个目标来研究选定的致肥药物对脂肪组织的直接影响：目标1，确定每种药物单独或与其他治疗联合使用如何影响hMSCs成为脂肪细胞或骨细胞的细胞命运决定；目的2，检查每种药物单独或与其他治疗联合如何在急性或慢性暴露下影响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，检查每种药物在急性或慢性暴露下对脂肪细胞中脂肪积累和脂溶率的潜在影响；目的4，探讨前3个目的中确定的药物体外致肥作用的分子机制。本研究将有助于了解已知致肥药物对脂肪稳态的潜在直接作用，并有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，以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致脂毒性。

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.