Inhibition of ALDH1A1 for the treatment of obesity

项目总结 我们的长期目标是开发安全有效的治疗肥胖症的药物。拟议的研究旨在 验证一个新的靶点ALDH1A1，它是脂肪中生成维甲酸(RA)的主要酶 组织，用于治疗肥胖症。RA是由三种主要的乙醛脱氢酶ALDH1A1， ALDH1A2和ALDH1A3在时间和空间上以不同的模式表达，并参与 包括发育、繁殖和免疫在内的各种过程。RA还调节相关基因的表达 在脂肪组织分化以及葡萄糖和脂肪代谢方面。在我们努力发展男性的过程中 使用减少睾丸中RA合成的小分子避孕药，我们观察到治疗的小鼠 使用ALDH1A同工酶的泛抑制剂Win 18,446，由于 脂肪组织块。这种减轻的体重增加可以通过与RA的共同治疗而逆转，这表明 ALDH1a抑制(RA减少)可用于体重调节。因此，我们测试了RA的疗效 利用饮食诱导肥胖的小鼠模型进行合成抑制，并发现Win 18,446对 减轻体重增加，尽管动物继续食用高脂肪饮食。其他人则有 研究表明，缺乏RA合成酶Aldh1a1，会改变肝脏和肝脏的能量代谢 脂肪组织由于组织维甲酸水平的变化(RA和视网膜)，从而保护小鼠免受饮食的影响- 诱导性肥胖。我们假设药物通过失活抑制RA的生物合成 ALDH1A1是治疗肥胖症的新靶点。为了测试这一点，在具体目标1中，我们将评估 Win 18,446作为肥胖症治疗的有效性和毒性，并将进一步确定其潜力 机制，包括肝脏、脂肪组织和肌肉中能量代谢的改变，增加 脂肪组织中的生热作用及其对成脂的影响。维甲酸的浓度和表达 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测。 以确定RA动态平衡的差异(视网膜和RA浓度)是否与 人体的体重指数。尽管Win 18,446是一种有希望的体重调节化合物，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 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ALDH1A1特异性抑制剂治疗肥胖症，最大限度地减少与 完全抑制维甲酸的合成。在具体目标3中，我们将测试我们的新ALDH1A1- 治疗小鼠肥胖的特异性抑制剂。拟议中的研究将确定一个新的治疗靶点。 肥胖有可能改善与肥胖相关的代谢异常。

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.