Almuraikhy Shamma, Alser Maha, Naja Khaled, Al-Malki Aisha, Mazloum Nayef A, Elrayess Mohamed A
Biomedical Research Center, Qatar University, Doha P.O. Box 2713, Qatar.
Department of Microbiology and Immunology, Weill Cornell Medicine-Qatar (WCM-Q), Qatar Foundation, Doha P.O. Box 24144, Qatar.
Cells. 2025 Jan 10;14(2):100. doi: 10.3390/cells14020100.
GATA-3 is a master regulator of preadipocyte differentiation and function. Pharmacological or genetic targeting of GATA-3 will allow us to understand the function of GATA-3 in regulating metabolism, insulin signaling, and inflammation. Pyrrothiogatain, a novel small molecule inhibitor of GATA family proteins, has emerged as a promising tool for modulating GATA-3 activity. This study aims to investigate the specificity of Pyrrothiogatain in regulating GATA-3-mediated preadipocyte differentiation and adipokine secretion under normal and pathological conditions. Wild-type and GATA-3 knockout 3T3-L1 cells were treated with different concentrations of Pyrrothiogatain in the presence and absence of 4-hydroxy-2-nonenal (4HNE), an inducer of oxidative stress and impairment of adipogenesis. As expected, GATA-3 knockout cells exhibited enhanced adipogenic capacity, characterized by increased cell and lipid droplet sizes, and upregulated expression of key adipogenic markers including CEBPβ, PPARγ, and PGC-1α. Pyrrothiogatain treatment reduced cell proliferation in both wild-type and GATA-3 knockout 3T3-L1 cells, but did not alter their adipogenic capacity. Furthermore, Pyrrothiogatain lowered secreted IL-6 levels and attenuated 4-HNE-induced TNF-α elevation in wild-type, but not in GATA-3 knockout cells. Co-treatment of 4-HNE and Pyrrothiogatain led to increased cell size, suggesting complex interactions between oxidative stress and GATA protein inhibition. This effect was similar to GATA-3 knockout cells, indicating Pyrrothiogatain's potential to modulate cellular stress responses independently of GATA-3 inhibition. These results reveal that Pyrrothiogatain's effects on adipocyte biology extend beyond simple GATA-3 inhibition. While GATA-3 knockout primarily affects adipogenesis, Pyrrothiogatain modulates inflammatory responses and potentially cellular stress mechanisms without directly impacting adipocyte differentiation. This study provides new insights into the multifaceted actions of Pyrrothiogatain and highlights its potential as a therapeutic agent for lowering inflammation and oxidative-stress-related aspects of metabolic disorders, distinct from the direct modulation of adipogenesis.
GATA-3是前脂肪细胞分化和功能的主要调节因子。对GATA-3进行药理学或基因靶向研究将使我们能够了解GATA-3在调节代谢、胰岛素信号传导和炎症方面的功能。吡咯硫代胍，一种新型的GATA家族蛋白小分子抑制剂，已成为调节GATA-3活性的一种有前景的工具。本研究旨在探讨吡咯硫代胍在正常和病理条件下调节GATA-3介导的前脂肪细胞分化和脂肪因子分泌的特异性。在存在和不存在4-羟基-2-壬烯醛（4HNE，一种氧化应激诱导剂和脂肪生成损伤剂）的情况下，用不同浓度的吡咯硫代胍处理野生型和GATA-3基因敲除的3T3-L1细胞。正如预期的那样，GATA-3基因敲除细胞表现出增强的脂肪生成能力，其特征是细胞和脂滴大小增加，以及关键脂肪生成标志物CEBPβ、PPARγ和PGC-1α的表达上调。吡咯硫代胍处理降低了野生型和GATA-3基因敲除的3T3-L1细胞的增殖，但没有改变它们的脂肪生成能力。此外，吡咯硫代胍降低了野生型细胞中分泌的IL-6水平，并减弱了4-HNE诱导的TNF-α升高，但在GATA-3基因敲除细胞中没有这种作用。4-HNE和吡咯硫代胍共同处理导致细胞大小增加，表明氧化应激和GATA蛋白抑制之间存在复杂的相互作用。这种效应与GATA-3基因敲除细胞相似，表明吡咯硫代胍有可能独立于GATA-3抑制来调节细胞应激反应。这些结果表明，吡咯硫代胍对脂肪细胞生物学的影响超出了简单的GATA-3抑制。虽然GATA-3基因敲除主要影响脂肪生成，但吡咯硫代胍调节炎症反应以及潜在的细胞应激机制，而不直接影响脂肪细胞分化。本研究为吡咯硫代胍的多方面作用提供了新的见解，并突出了其作为治疗剂降低代谢紊乱中炎症和氧化应激相关方面的潜力，这与直接调节脂肪生成不同。
