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.

项目概要 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 验证新靶标 ALDH1A1，这是脂肪中生成视黄酸 (RA) 的主要酶 组织，用于治疗肥胖症。 RA 由三种主要醛脱氢酶 ALDH1A1 合成， ALDH1A2 和 ALDH1A3 以时间和空间独特的模式表达并参与 过程包括发育、繁殖和免疫。 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。在我们努力培养男性的过程中 使用小分子避孕药减少睾丸中 RA 的合成，我们观察到接受治疗的小鼠 使用 WIN 18,446（一种 ALDH1A 同工酶的泛抑制剂），由于 ALDH1A 同工酶的减少，体重增加较低 脂肪组织块。与 RA 联合治疗可以逆转体重增加的减弱，这表明 ALDH1A 抑制（RA 减少）可用于体重调节。因此，我们测试了 RA 的功效 使用饮食诱导肥胖的小鼠模型进行合成抑制，发现 WIN 18,446 有效 尽管动物继续食用高脂肪饮食，但体重增加却减弱了。其他人有 证明 RA 合成酶 Aldh1a1 的缺失会改变肝脏的能量代谢， 由于组织类视黄醇水平（RA和视网膜）的变化，脂肪组织中的脂肪组织发生变化，从而保护小鼠免受饮食影响 诱发肥胖。我们假设通过灭活 RA 生物合成的药理抑制作用 ALDH1A1 是治疗肥胖的新靶点。为了测试这一点，在具体目标 1 中，我们将评估 WIN 18,446 作为肥胖治疗的功效和毒性，还将确定潜在的 机制，包括肝脏、脂肪组织和肌肉能量代谢的改变，增加 脂肪组织的产热作用及其对脂肪生成的影响。类维生素A浓度和表达 三种 RA 合成酶的模式也将在人类内脏和皮下脂肪中进行检查 组织以确定 RA 稳态（视网膜和 RA 浓度）的差异是否与 人类的体重指数。尽管 WIN 18,446 是一种很有前景的体重调节化合物，但它的 抑制所有三种 RA 合成酶和其他 ALDH 酶已被证明会导致不必要的后果 副作用，例如抑制精子发生和酒精毒性。在具体目标 2 中，我们建议 开发 ALDH1A1 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 完全抑制视黄酸合成。在具体目标 3 中，我们将测试新 ALDH1A1 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 肥胖有可能改善与肥胖相关的代谢异常。