Department of Anatomy, Physiology and Pharmacology, College of Veterinary Medicine, Auburn University, Auburn, Alabama, USA.
Prog Mol Biol Transl Sci. 2014;121:217-66. doi: 10.1016/B978-0-12-800101-1.00007-7.
The epidemic of obesity and its association with insulin resistance, glucose intolerance, hypertension, and dyslipidemia, collectively known as the metabolic syndrome or syndrome X, is one of the most challenging health problems facing industrialized countries. The nuclear receptors, peroxisome proliferator-activated receptors (PPARs alpha (α), beta (β) also known as delta (δ), and gamma (γ)), have well-documented roles in lipid and glucose metabolism. Pharmacologically, PPARα is activated by fibrate hypolipidemic drugs, whereas PPARγ is activated by insulin sensitizers thiazolidinediones (TZDs). No marketed drug is yet available for PPARβ(δ). The identification of fibrates and TZDs as respective ligands for PPARα and PPARγ was a groundbreaking finding that sparked notable pharmaceutical interest in PPARs as potential drug targets for treatment of the metabolic syndrome. Limiting side effects associated with clinical use of TZDs have emerged in recent years. New and novel PPAR drugs with broad safety margins and therapeutic potentials for the metabolic syndrome are in development. These include partial, dual, or pan PPAR agonists; PPAR antagonists; and selective PPAR modulators. The objective of this chapter is to highlight the therapeutic benefits of targeting more than one PPAR subtype in the treatment of the metabolic syndrome. The pros and cons observed during clinical use of TZDs and the strategies and progress made in the production of new generations of safe and effective PPAR ligands are discussed.
肥胖症及其与胰岛素抵抗、葡萄糖耐量异常、高血压和血脂异常的关联，统称为代谢综合征或综合征 X，是工业化国家面临的最具挑战性的健康问题之一。核受体，过氧化物酶体增殖物激活受体（PPARs）α（α）、β（β）也称为δ（δ）和γ（γ），在脂质和葡萄糖代谢中具有明确的作用。药理学上，PPARα 被纤维酸类降脂药物激活，而 PPARγ 则被胰岛素增敏剂噻唑烷二酮（TZDs）激活。目前尚无市售药物可用于 PPARβ（δ）。发现纤维酸类药物和 TZDs 分别是 PPARα 和 PPARγ 的配体，这是一项开创性的发现，激发了人们对 PPAR 作为治疗代谢综合征的潜在药物靶点的浓厚兴趣。近年来，与 TZDs 临床应用相关的限制副作用已经出现。正在开发具有广泛安全边际和治疗代谢综合征潜力的新型和新型 PPAR 药物。这些包括部分、双重或全 PPAR 激动剂；PPAR 拮抗剂；和选择性 PPAR 调节剂。本章的目的是强调针对代谢综合征的一种以上 PPAR 亚型治疗的治疗益处。讨论了在 TZDs 的临床应用中观察到的优缺点，以及在生产新一代安全有效的 PPAR 配体方面取得的策略和进展。
