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。拟议的研究旨在 验证一个新的目标，ALDH 1A 1，主要酶参与产生视黄酸（RA）在脂肪 用于治疗肥胖症。RA由三种主要的醛脱氢酶ALDH 1A 1， ALDH 1A 2和ALDH 1A 3以时间和空间上不同的模式表达，并参与 包括发育、生殖和免疫等过程。RA还调节相关基因的表达， 脂肪组织分化以及葡萄糖和脂质代谢。在我们努力发展男性 使用减少睾丸中RA合成的小分子避孕药，我们观察到， WIN 18，446是ALDH 1A同工酶的泛抑制剂，由于WIN 18，446降低了体重增加， 脂肪组织质量。这种减弱的体重增加通过与RA联合治疗而逆转，这表明， ALDH 1A抑制（RA减少）可用于体重调节。因此，我们测试了RA的疗效 使用饮食诱导的肥胖症的鼠模型进行合成抑制，并发现WIN 18，446在 尽管动物持续食用高脂肪饮食，但体重增加减少。其他人已经 证明了RA合成酶Aldh 1a 1的缺乏改变了肝脏的能量代谢， 由于组织类维生素A水平（RA和视网膜）的变化，脂肪组织，从而保护小鼠免受饮食- 诱发性肥胖我们假设，通过灭活RA的生物合成， ALDH 1A 1是治疗肥胖症的新靶点。为了验证这一点，在具体目标1中，我们将评估 WIN 18，446作为肥胖治疗的有效性和毒性，并将另外确定 机制，包括肝脏、脂肪组织和肌肉中能量代谢的改变， 脂肪组织中的产热和对脂肪形成的影响。维甲酸浓度和表达 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 人体的体重指数虽然WIN 18，446是一种有前途的体重调节化合物， 抑制所有三种RA合成酶和其它ALDH酶已经显示出引起不希望的 副作用，如抑制精子生成和酒精中毒。在具体目标2中，我们建议 开发ALDH 1A 1特异性抑制剂来治疗肥胖，最大限度地减少与肥胖相关的潜在副作用。 完全抑制视黄酸的合成。在具体目标3中，我们将测试我们的新ALDH 1A 1的功效- 用于治疗小鼠肥胖症的特异性抑制剂。拟议的研究将确定一个新的治疗目标 具有改善与肥胖相关的代谢异常的潜力。