Validation of ALDH1A1 as a target for the treatment of obesity: effects of ALDH1A1 inhibition on energy metabolism

验证 ALDH1A1 作为肥胖治疗靶点：抑制 ALDH1A1 对能量代谢的影响

• 批准号: 10681349
• 负责人: JISUN PAIK
• 金额: $ 39.41万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10681349
• 关键词: ALDH1A2 gene; Acceleration; Adipocytes; Adipose tissue; Adult; Affect; Agreement; Alcohols; American; Animals; Attenuated; Biological Assay; Biological Markers; Biology; Birth; Body Temperature; Body Weight decreased; Calories; Clinical; Clinical Pathology; Clinical Protocols; Complement; Contraceptive Usage; Data; Desire for food; Development; Diet; Embryo; Energy Metabolism; Energy consumption; Enzyme Inhibitor Drugs; Enzymes; Fatty Acids; Fatty acid glycerol esters; Female; Future; Gene Expression; Glucose; Goals; Health; Hepatic; High Fat Diet; High Prevalence; Histopathology; Human; Hypertrophy; Immunity; Knowledge; Label; Lipoidosis; Liver; Male Contraceptive Agents; Mediating; Metabolic; Methods; Modeling; Mus; Muscle; Obese Mice; Obesity; Oral; Organ; Pathology; Pattern; Pharmaceutical Preparations; Pharmacodynamics; Pharmacological Treatment; Phenotype; Physiology; Public Health; Pyruvate; Regression Analysis; Regulation; Reporter; Reproduction; Resistance; Retinoids; Role; Safety; Specificity; Spermatogenesis; Statistical Models; Systems Biology; Testing; Testis; Tissue Differentiation; Tissues; Toxic effect; Treatment Efficacy; Treatment-related toxicity; Tretinoin; United States; Validation; Visceral; Vitamin A; Weight; Weight Gain; aldehyde dehydrogenases; biomarker identification; comorbidity; diet-induced obesity; dietary; efficacy evaluation; efficacy testing; feeding; glucose metabolism; improved; in vivo; inhibitor; innovation; insight; lipid biosynthesis; lipid metabolism; male; metabolic profile; metabolomics; mouse model; new therapeutic target; novel; novel therapeutics; obese patients; obesity treatment; pharmacologic; potential biomarker; prototype; response; sex; side effect; small molecule; translational potential

PROJECT SUMMARY Our long-term goal is to develop safe and effective drugs to treat obesity. We propose to validate ALDH1A1 as a new drug target for obesity treatment by testing the anti-obesity efficacy of a novel inhibitor of this enzyme, N42, that was recently developed by our group. Retinoic acid (RA), a metabolite of vitamin A, is synthesized by three aldehyde dehydrogenases, ALDH1A1, ALDH1A2, and ALDH1A3, that are expressed in temporally and spatially distinct yet sometimes overlapping patterns in a tissue- and developmental stage-dependent manner. ALDH1A1 is the major RA synthesis enzyme in two metabolically important tissues, liver and adipose, where RA is known to regulate expression of genes involved in glucose and lipid metabolism and adipose tissue differentiation. Aldh1a1-/- mice develop normally, are healthy and fertile, and are also protected from developing diet-induced obesity. In agreement with observations in Aldh1a1-/- mice, we demonstrated that mice treated with WIN 18,446, a pan-inhibitor of ALDH1A enzymes, had lower weight gain due to a decrease in adipose tissue mass, demonstrating the feasibility of using pharmacological inhibitors of ALDH1A to treat obesity. Although WIN 18,446 treatment is promising for weight suppression, it inhibits other RA synthesis enzymes as well as ALDH2, causing unwanted side effects such as reversible spermatogenesis inhibition and alcohol intolerance. Therefore, we developed compounds that specifically inhibit ALDH1A1 and now propose to evaluate the efficacy and potential toxicity of a novel ALDH1A1-specific inhibitor, N42, for treatment of obesity and to determine mechanisms by which ALDH1A1 regulates weight gain by using comprehensive studies of gene expression and metabolite changes in response to ALDH1A1 loss. In Aim 1, we will determine if N42 treatment can (1) suppress weight gain in obese mice when they are continuously fed a high fat diet and (2) accelerate weight loss in obese mice when they are provided reduced calorie diet. We will also investigate potential organ toxicity of N42 treatment using standard, well-established protocols of clinical and toxicologic pathology. Metabolic changes associated with ALDH1A1 loss (N42 treatment or Aldh1a1-/- mice) will be comprehensively investigated using global metabolomics and gene expression studies. Phenotypic parameters including metabolites, gene expression, retinoid levels etc. will be associated with N42-mediated efficacy to identify potential biomarkers for future clinical use of this compound. In Aim 2, the role of ALDH1A1 in liver and adipose tissues will be further explored using tissue-specific Aldh1a1-/- mice. We will also determine how ALDH1A1 loss in adults alters adipogenesis and adipocyte hypertrophy using an adipocyte linage mouse model. Finally, we will identify tissue-autonomous functions of ALDH1A1 by combining a novel perifusion method, metabolomics, and systems-biology approaches. Successful completion of the proposed studies will validate ALDH1A1 as a novel target to treat obesity and provide a potential prototype drug.

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。我们建议将ALDH1A1验证为 通过测试这种酶的一种新的抑制剂的抗肥胖效果来治疗肥胖的新药靶点， N42，这是我们团队最近开发的。维甲酸(RA)是维生素A的代谢物，由 三种乙醛脱氢酶，ALDH1A1，ALDH1A2和ALDH1A3，在时间和 以依赖于组织和发育阶段的方式在空间上不同但有时重叠的图案。 ALDH1A1是肝脏和脂肪这两个代谢重要组织中的主要RA合成酶，其中RA 已知可调节涉及糖脂代谢和脂肪组织的基因的表达 差异化。ALDH1A1-/-小鼠发育正常，健康且有生育能力，并受到保护 发展饮食诱导的肥胖。与在Aldh1a1-/-小鼠中的观察结果一致，我们证明了 用ALDH1A酶的泛抑制剂Win 18,446治疗的小鼠体重增加较少，这是因为 脂肪组织块，证明使用ALDH1a药物抑制剂治疗肥胖的可行性。 尽管Win 18,446治疗有望抑制体重，但它抑制了其他RA合成酶，如 和ALDH2一样，会导致可逆性生精抑制和酒精等不良副作用 不宽容。因此，我们开发了专门抑制ALDH1A1的化合物，现在提出 评价一种新型ALDH1A1特异性抑制剂N42治疗高血压的疗效和潜在毒性 肥胖和确定ALDH1A1调节体重增加的机制 ALDH1A1缺失后基因表达和代谢物变化的综合研究。在……里面 目的1，我们将确定N42治疗是否可以(1)抑制肥胖小鼠的体重增加 喂食高脂肪饮食和(2)当提供低卡路里饮食时，加速肥胖小鼠的体重减轻。我们 还将使用标准的、完善的临床方案来调查N42治疗的潜在器官毒性 和毒理病理学。与ALDH1A1缺失相关的代谢变化(N42治疗或Aldh1a1-/-小鼠) 将利用全球新陈代谢组学和基因表达研究进行全面研究。表型 代谢物、基因表达、维甲酸水平等参数将与N42介导的 确定该化合物未来临床使用的潜在生物标记物的有效性。在目标2中，ALDH1A1的作用 将使用组织特异性Aldh1a1-/-小鼠进一步探索肝脏和脂肪组织中的基因。我们还将确定 利用脂肪细胞系小鼠研究成人ALDH1A1缺失如何改变脂肪形成和脂肪细胞肥大 模特。最后，我们将通过结合一种新的灌流来鉴定ALDH1A1的组织自主功能 方法、代谢组学和系统生物学方法。成功完成拟议的研究将 验证ALDH1A1作为治疗肥胖症的新靶点，并提供潜在的原型药物。