Department of Pharmacy, "G. d'Annunzio" University, Via dei Vestini 31, 66100 Chieti, Italy.
Molecules. 2022 Jul 30;27(15):4882. doi: 10.3390/molecules27154882.
PPARγ agonists are implicated in the regulation of diabetes and metabolic syndrome and have therapeutic potential in brain disorders. PPARγ modulates appetite through its central effects, especially on the hypothalamic arcuate nucleus (ARC). Previous studies demonstrated that the small molecule GL516 is a PPARγ agonist able to reduce oxidative stress and apoptosis with a potential neuroprotective role. Herein, we investigated the effects of GL516, in vitro and ex vivo, on the levels of hypothalamic dopamine (DA) and serotonin (5-HT). The gene expressions of neuropeptide Y, CART, AgRP, and POMC, which play master roles in the neuroendocrine regulation of feeding behavior and energy balance, were also evaluated. HypoE22 cells were treated with HO (300 μM) for 2 h e 30' and with different concentrations of GL516 (1 nM-100 µM). The cell viability was evaluated after 24 and 48 h of culturing using the MTT test. DA and 5-HT levels in the HypoE22 cell supernatants were analyzed through HPLC; an ex vivo study on isolated hypothalamic specimens challenged with scalar concentrations of GL516 (1-100 µM) and with pioglitazone (10 µM) was carried out. The gene expressions of CART, NPY, AgRP, and POMC were also determined by a quantitative real-time PCR. The results obtained showed that GL516 was able to reduce DA and 5-HT turnover; moreover, it was effective in stimulating NPY and AgRP gene expressions with a concomitant reduction in CART and POMC gene expressions. These results highlight the capability of GL516 to modulate neuropeptide pathways deeply involved in appetite control suggesting an orexigenic effect. These findings emphasize the potential use of GL516 as a promising candidate for therapeutical applications in neurodegenerative diseases associated with the reduction in food intake and stimulation of catabolic pathways.
过氧化物酶体增殖物激活受体γ激动剂参与糖尿病和代谢综合征的调节，并且在脑部疾病中有治疗潜力。过氧化物酶体增殖物激活受体γ通过其中枢作用，特别是对下丘脑弓状核（ARC）的作用来调节食欲。先前的研究表明，小分子 GL516 是一种过氧化物酶体增殖物激活受体γ激动剂，能够减少氧化应激和细胞凋亡，具有潜在的神经保护作用。在此，我们研究了 GL516 在体外和离体下丘脑组织中的作用，以评估其对下丘脑多巴胺（DA）和 5-羟色胺（5-HT）水平的影响。还评估了神经肽 Y、CART、AgRP 和 POMC 的基因表达，这些基因在神经内分泌调节摄食行为和能量平衡方面发挥着主要作用。HypoE22 细胞用 HO（300 μM）处理 2 小时，然后用不同浓度的 GL516（1 nM-100 μM）处理 30'。用 MTT 试验评估培养 24 和 48 小时后的细胞活力。通过 HPLC 分析 HypoE22 细胞上清液中的 DA 和 5-HT 水平；对离体下丘脑标本进行了一项研究，用 GL516（1-100 μM）和吡格列酮（10 μM）的标度浓度进行了挑战。还通过定量实时 PCR 确定了 CART、NPY、AgRP 和 POMC 的基因表达。结果表明，GL516 能够减少 DA 和 5-HT 的转化；此外，它能够有效地刺激 NPY 和 AgRP 基因的表达，同时降低 CART 和 POMC 基因的表达。这些结果强调了 GL516 调节食欲控制中涉及的神经肽途径的能力，表明其具有食欲刺激作用。这些发现强调了 GL516 作为治疗与食物摄入减少和代谢途径刺激相关的神经退行性疾病的有前途的候选药物的潜在用途。
