Institute of Genetics and Biophysics "Adriano Buzzati-Traverso", CNR, Via P. Castellino 111, 80131, Naples, Italy.
Department of Science and Technology, University of Naples "Parthenope", 80131, Naples, Italy.
Curr Diab Rep. 2021 Apr 18;21(6):18. doi: 10.1007/s11892-021-01385-5.
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.
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. 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.
针对转录因子 PPARγ 的全合成和部分合成激动剂包含在 FDA 批准的胰岛素增敏药物中，用于治疗与代谢综合征相关的功能障碍。在这里，我们讨论了 PPARG 遗传变异与药物疗效之间的关系，以及可变剪接和翻译后修饰作为 PPARγ 信号复杂性和合成 PPARγ 配体作用的贡献因素。
PPARγ 调节几个靶基因的转录，这些基因控制脂肪细胞分化以及葡萄糖和脂质代谢、胰岛素敏感性和炎症途径。这些多效性功能使 PPARγ 在全身代谢的生理调节以及代谢紊乱的发病机制中具有重要意义。因此，PPARG 基因突变、核苷酸变异和翻译后修饰与脂肪组织紊乱以及相关的胰岛素抵抗和 2 型糖尿病（T2D）风险相关。此外，PPARγ 可变剪接异构体（主要在人脂肪组织中表达的显性负性异构体）与 PPARγ 活性受损和脂肪组织功能障碍有关。因此，有助于 PPARγ 信号复杂性的多个调节水平可能解释了 PPARγ 激动剂的有益和不利影响。进一步的靶向分析，考虑到所有这些方面，对于更好地破译 PPARγ 在人类病理生理学中的作用，特别是在胰岛素抵抗和 T2D 中，是必要的。全合成和部分合成的 PPARγ 激动剂的治疗潜力突出了该核受体的临床意义。PPARG 突变、多态性、可变剪接异构体和翻译后修饰可能有助于代谢紊乱的发病机制，也影响药物治疗的反应性。因此，在当前基于证据的个性化糖尿病管理趋势的背景下，我们强调需要破译 PPARγ 信号的复杂调节，为胰岛素抵抗和 T2D 患者的个体化治疗铺平道路。
