Purpose of Review

Full and partial synthetic agonists targeting the transcription factor PPARγ are contained in FDA-approved insulin-sensitizing drugs and used for the treatment of metabolic syndrome-related dysfunctions. Here, we discuss the association between PPARG genetic variants and drug efficacy, as well as the role of alternative splicing and post-translational modifications as contributors to the complexity of PPARγ signaling and to the effects of synthetic PPARγ ligands.

Recent Findings

PPARγ regulates the transcription of several target genes governing adipocyte differentiation and glucose and lipid metabolism, as well as insulin sensitivity and inflammatory pathways. These pleiotropic functions confer great relevance to PPARγ in physiological regulation of whole-body metabolism, as well as in the etiology of metabolic disorders. Accordingly, PPARG gene mutations, nucleotide variations, and post-translational modifications have been associated with adipose tissue disorders and the related risk of insulin resistance and type 2 diabetes (T2D). Moreover, PPARγ alternative splicing isoforms—generating dominant-negative isoforms mainly expressed in human adipose tissue—have been related to impaired PPARγ activity and adipose tissue dysfunctions. Thus, multiple regulatory levels that contribute to PPARγ signaling complexity may account for the beneficial as well as adverse effects of PPARγ agonists. Further targeted analyses, taking into account all these aspects, are needed for better deciphering the role of PPARγ in human pathophysiology, especially in insulin resistance and T2D.

Summary

The therapeutic potential of full and partial PPARγ synthetic agonists underlines the clinical significance of this nuclear receptor. PPARG mutations, polymorphisms, alternative splicing isoforms, and post-translational modifications may contribute to the pathogenesis of metabolic disorders, also influencing the responsiveness of pharmacological therapy. Therefore, in the context of the current evidence-based trend to personalized diabetes management, we highlight the need to decipher the intricate regulation of PPARγ signaling to pave the way to tailored therapies in patients with insulin resistance and T2D.

中文翻译：

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PPARγ和糖尿病：超越基因组并迈向个性化医学

审查目的

FDA批准的胰岛素敏感性药物中包含靶向转录因子PPARγ的全部和部分合成激动剂，并用于治疗代谢综合征相关的功能障碍。在这里，我们讨论了PPARG遗传变异与药物功效之间的关联，以及选择性剪接和翻译后修饰作为PPARγ信号传导复杂性和合成PPARγ配体作用的贡献者的作用。

最近的发现

PPARγ调节控制脂肪细胞分化，葡萄糖和脂质代谢以及胰岛素敏感性和炎症途径的几个靶基因的转录。这些多效性功能在全身代谢的生理调节以及代谢疾病的病因学方面与PPARγ密切相关。因此，PPARG基因突变，核苷酸变异和翻译后修饰与脂肪组织疾病以及胰岛素抵抗和2型糖尿病（T2D）的相关风险有关。此外，PPARγ选择性剪接同工型（主要在人体脂肪组织中表达的显性负性同工型）与PPARγ活性受损和脂肪组织功能障碍有关。因此，促成PPARγ信号传导复杂性的多个调节水平可解释PPARγ激动剂的有益作用和不利作用。考虑到所有这些方面，需要进行进一步的有针对性的分析，以更好地理解PPARγ在人体病理生理中的作用，尤其是在胰岛素抵抗和T2D中的作用。

概括

完全和部分PPARγ合成激动剂的治疗潜力突显了这种核受体的临床意义。PPARG突变，多态性，替代剪接亚型和翻译后修饰可能有助于代谢紊乱的发病机理，也影响药物治疗的反应性。因此，在当前以证据为基础的个性化糖尿病治疗趋势中，我们强调需要破译PPARγ信号的复杂调控，为胰岛素抵抗和T2D患者的定制疗法铺平道路。