二硝基苯酚及相关药物治疗肥胖及相关代谢性疾病的研究进展

Research progress on therapeutic implications of dinitrophenol and related drugs in obesity and associated metabolic diseases

肥胖及其相关代谢改变是心血管疾病等多种慢性复杂性疾病的主要危险因素,有效控制肥胖及相关代谢改变具有重要的临床意义。线粒体解偶联可促进能量支出和消耗,已成为干预肥胖症的新药物靶点。线粒体解偶联剂2,4-二硝基苯酚(DNP)通过线粒体氧化磷酸化解偶联、抑制脂肪组织炎症、促进脑源性神经营养因子的表达等,起到降低体重及改善糖脂代谢的作用。然而,DNP可引起产热过多、乳酸堆积及电解质紊乱等多种不良反应,限制了其临床应用。近年来,通过改造药物结构、改进药物递送等方法,研发了DNP-甲基醚,DNP控释制剂、DNP液晶凝胶载体药物,以及DNP联合丙酮酸脱氢酶激酶抑制剂用药策略,提高了其有效性和安全性,为临床治疗肥胖及相关代谢性疾病提供了新的手段。

Obesity and associated metabolic disorders constitute the major risk factors for the development of a myriad of health-threatening chronic and complex diseases including cardiovascular diseases,so effective control of obesity and related metabolic changes has important clinical significance.Mitochondrial uncoupling leads to enhanced energy expenditure and therefore has emerged as a new target for the treatment of obesity and associated metabolic disorders.2,4-Dinitrophenol(DNP),a mitochondrial uncoupler,can reduce weight and improve glucose and lipid metabolism through mitochondrial oxidative phosphorylation uncoupling,inhibition of inflammation in the adipose tissue,induction of the expression of brain-derived neurotrophic factor,and so on.However,the clinical application of DNP remains limited due to its adverse reactions,which include excessive heat production,lactic acid accumulation and electrolyte disturbance,etc.Recently,DNP-methyl ether,controlled-release formulation of DNP,DNP carried by liquid crystal gel,and combined medication strategy of DNP and pyruvate dehydrogenase kinase inhibitor have been developed by drug structure modification and drug delivery improvement.The improved efficacy and safety of DNP related drugs may provide new means for the clinical treatment of obesity and related metabolic diseases.