Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Département de médecine, Faculté de Médecine, Université Laval, Québec, Canada; Institut sur la Nutrition et les Aliments Fonctionnels (INAF), Centre NUTRISS, Université Laval, Québec, Canada; Canada Excellence Research Chair on the Microbiome-Endocannabinoidome Axis in Metabolic Health (CERC-MEND), Université Laval, Québec, Canada.
Centre de Recherche de l'Institut Universitaire de Cardiologie et de Pneumologie de Québec (CRIUCPQ), Département de médecine, Faculté de Médecine, Université Laval, Québec, Canada.
J Lipid Res. 2023 Nov;64(11):100444. doi: 10.1016/j.jlr.2023.100444. Epub 2023 Sep 18.
White adipose tissue regulation is key to metabolic health, yet still perplexing. The chief endocannabinoid anandamide metabolite, prostaglandin F ethanolamide (PGFEA), inhibits adipogenesis, that is, the formation of mature adipocytes. We observed that adipocyte progenitor cells-preadipocytes-following treatment with PGFEA yielded larger pellet sizes. Thus, we hypothesized that PGFEA might augment preadipocyte proliferation. Cell viability MTT and crystal violet assays, cell counting, and 5-bromo-2'-deoxyuridine incorporation in cell proliferation ELISA analyses confirmed our prediction. Additionally, we discovered that PGFEA promotes cell cycle progression through suppression of the expression of cell cycle inhibitors, p21 and p27, as shown by flow cytometry and qPCR. Enticingly, concentrations of this compound that showed no visible effect on cell proliferation or basal transcriptional activity of peroxisome proliferator-activated receptor gamma could, in contrast, reverse the anti-proliferative and peroxisome proliferator-activated receptor gamma-transcription activating effects of rosiglitazone (Rosi). MTT and luciferase reporter examinations supported this finding. The PGFEA pharmaceutical analog, bimatoprost, was also investigated and showed very similar effects. Importantly, we suggest the implication of the mitogen-activated protein kinase pathway in these effects, as they were blocked by the selective mitogen-activated protein kinase kinase inhibitor, PD98059. We propose that PGFEA is a pivotal regulator of white adipose tissue plasticity, acting as a regulator of the preadipocyte pool in adipose tissue.
白色脂肪组织的调节是代谢健康的关键，但仍然令人费解。主要的内源性大麻素代谢物，前列腺素 F 乙醇酰胺（PGFEA），抑制脂肪生成，即成熟脂肪细胞的形成。我们观察到，脂肪细胞前体细胞-前脂肪细胞-在 PGFEA 处理后产生更大的细胞团大小。因此，我们假设 PGFEA 可能增强前脂肪细胞增殖。细胞活力 MTT 和结晶紫分析、细胞计数和细胞增殖 ELISA 分析中的 5-溴-2'-脱氧尿苷掺入证实了我们的预测。此外，我们发现 PGFEA 通过抑制细胞周期抑制剂 p21 和 p27 的表达来促进细胞周期进程，如流式细胞术和 qPCR 所示。有趣的是，这种化合物的浓度对细胞增殖或过氧化物酶体增殖物激活受体 γ 的基础转录活性没有明显影响，但可以逆转罗格列酮（Rosi）的抗增殖和过氧化物酶体增殖物激活受体 γ-转录激活作用。MTT 和荧光素酶报告实验支持了这一发现。PGFEA 的药物类似物，比马前列素，也进行了研究，显示出非常相似的效果。重要的是，我们建议丝裂原激活的蛋白激酶途径在这些作用中的意义，因为它们被丝裂原激活的蛋白激酶激酶抑制剂 PD98059 阻断。我们提出 PGFEA 是白色脂肪组织可塑性的关键调节剂，作为脂肪组织中前脂肪细胞池的调节剂。
