Inhibition of ALDH1A1 for the treatment of obesity

抑制 ALDH1A1 治疗肥胖

• 批准号: 9517371
• 负责人: JISUN PAIK
• 金额: $ 31.1万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-22 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9517371
• 关键词: ALDH1A2 gene; Adipocytes; Adipose tissue; Adult; Adverse effects; Affect; American; Anabolism; Animals; Attenuated; Biological Assay; Body Weight decreased; Body mass index; Characteristics; Comorbidity; Computer Simulation; Consumption; Contraceptive Usage; Crystallization; Data; Development; Diet; Drug Kinetics; Energy Metabolism; Enzymes; Ethanol toxicity; Excretory function; Gene Expression; Gluconeogenesis; Goals; High Fat Diet; High Prevalence; Homeostasis; Human; Immunity; In Vitro; Inflammation; Isoenzymes; Knock-out; Lead; Lipolysis; Liver; Male Contraceptive Agents; Metabolic; Metabolism; Molecular Models; Mus; Muscle; Obese Mice; Obesity; Oxidative Phosphorylation; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacological Treatment; Pharmacology; Phenotype; Process; Public Health; Regulation; Reproduction; Research; Retinal; Retinoids; Role; Safety; Specificity; Spermatogenesis; Structure-Activity Relationship; Testing; Testis; Thermogenesis; Tissue Differentiation; Tissues; Toxic effect; Tretinoin; Triglycerides; United States; Visceral; Weight; Weight Gain; Work; aldehyde dehydrogenases; attenuation; base; design; efficacy testing; enzyme structure; glucose metabolism; human tissue; improved; inhibitor/antagonist; lipid biosynthesis; lipid metabolism; molecular modeling; mouse model; novel; obesity treatment; pharmacophore; screening; small molecule; small molecule inhibitor; subcutaneous

PROJECT SUMMARY Our long-term goal is to develop safe and effective drugs to treat obesity. The proposed studies are aimed at validating a new target, ALDH1A1, the major enzyme involved in generating retinoic acid (RA) in adipose tissues, for the treatment of obesity. RA is synthesized by three main aldehyde dehydrogenases, ALDH1A1, ALDH1A2, and ALDH1A3 that are expressed in temporally and spatially distinctive patterns and are involved in processes including development, reproduction and immunity. RA also regulates expression of genes involved in adipose tissue differentiation as well as glucose and lipid metabolism. During our efforts to develop male contraceptives using small molecules that reduce RA synthesis in the testes, we observed that mice treated with WIN 18,446, a pan-inhibitor of ALDH1A isozymes, had lower body weight gain due to a decrease in adipose tissue mass. This attenuated weight gain was reversed by co-treatment with RA, suggesting that ALDH1A inhibition (RA reduction) could be used for weight regulation. Thus, we tested the efficacy of RA synthesis inhibition using a murine model of diet-induced obesity and found that WIN 18,446 is effective in attenuating weight gain despite the animals’ continued consumption of a high fat diet. Others have demonstrated that the absence of the RA synthesizing enzyme, Aldh1a1, alters energy metabolism in liver and adipose tissues due to changes in tissue retinoid levels (RA and retinal) and thus, protecting mice against diet- induced obesity. We hypothesize that pharmacological inhibition of RA biosynthesis by inactivating ALDH1A1 is a novel target for the treatment of obesity. To test this, in Specific Aim 1, we will evaluate efficacy and toxicity of WIN 18,446 as an obesity treatment and will additionally determine potential mechanisms, including alterations in energy metabolism in liver, adipose tissues and muscles, increased thermogenesis in adipose tissue and effects on adipogenesis. Retinoid concentrations and the expression pattern of the three RA synthesis enzymes will also be examined in human visceral and subcutaneous adipose tissues to determine whether differences in RA homeostasis (retinal and RA concentrations) correlate with body mass index in humans. Although WIN 18,446 is a promising compound for weight regulation, its inhibition of all three RA synthesis enzymes and other ALDH enzymes has been shown to cause unwanted side effects such as inhibition of spermatogenesis and alcohol toxicity. In Specific Aim 2, we propose to develop ALDH1A1 specific inhibitors to treat obesity, minimizing the potential side effects associated with complete inhibition of retinoic acid synthesis. In Specific Aim 3, we will test the efficacy of our new ALDH1A1- specific inhibitors for the treatment of obesity in mice. The proposed studies will identify a novel target to treat obesity with the potential to improve metabolic abnormalities associated with obesity.

项目摘要 我们的长期目标是开发安全有效的药物来治疗肥胖症。拟议的研究针对 验证一个新靶AldH1A1，脂肪中涉及视黄酸（RA）的主要酶 组织，用于治疗肥胖症。 RA由三个主要醛脱氢酶AldH1A1，AldH1A1合成 AldH1a2和Aldh1a3以暂时和空间独特的模式表示，并参与 包括开发，繁殖和免疫力在内的过程。 RA还调节所涉及的基因的表达 在脂肪组织分化以及葡萄糖和脂质代谢中。在我们发展男性的过程中 避孕药使用小分子减少了测试中的RA合成，我们观察到治疗的小鼠 赢得18,446（ALDH1A同工酶的泛抑制剂），体重增加较低，这是由于减少 脂肪组织质量。这种减弱的体重增加通过与RA共同治疗逆转了，这表明 ALDH1A抑制（减少）可用于调节体重。那我们测试了RA的效率 使用饮食引起的肥胖症的鼠模型抑制抑制 减轻体重增加目的地，动物继续消耗高脂饮食。其他人有 证明不存在RA合成酶，ALDH1A1，改变了肝脏中的能量代谢 由于组织类维生素类似水平（RA和视网膜）的变化而导致的脂肪时间，因此可以保护小鼠免受饮食的影响 诱发肥胖。我们假设药物对RA生物合成的抑制 ALDH1A1是治疗肥胖症的新目标。为了测试这一点，在特定的目标1中，我们将评估 胜利的功效和毒性为18,446作为目标治疗，还将确定潜力 机制，包括肝脏组织和肌肉中能量代谢的改变，增加了 脂肪组织中的热发生以及对脂肪形成的影响。视网膜类似浓度和表达 还将在人内脏和皮下脂肪中检查三种RA合成酶的模式 组织以确定RA稳态（视网膜和RA浓度）的差异是否与 人类体重指数。尽管Win 18,446是体重法规的有前途的化合物，但 抑制所有三种RA合成酶和其他ALDH酶已被证明会引起不必要的 副作用，例如抑制精子发生和酒精毒性。在特定目标2中，我们建议 开发aldh1a1特异性抑制剂来治疗肥胖症，最大程度地减少与之相关的潜在副作用 视黄酸合成的完全抑制。在特定的目标3中，我们将测试我们新的Aldh1a1-的效率 特异性抑制剂治疗小鼠肥胖症。拟议的研究将确定一个新的目标来治疗 肥胖具有改善与肥胖相关的代谢异常的潜力。