Department of Internal Medicine, Division of Endocrinology and Diabetes, University Hospital Wuerzburg, University of Wuerzburg, 97080 Wuerzburg, Germany.
Institute of Pathology, University of Wuerzburg, 97070 Wuerzburg, Germany.
Nutrients. 2024 Mar 21;16(6):904. doi: 10.3390/nu16060904.
(1) Background: Modulators of the Neuropeptide Y (NPY) system are involved in energy metabolism, but the effect of NPY receptor antagonists on metabolic-dysfunction-associated steatotic liver disease (MASLD), a common obesity-related comorbidity, are largely unknown. In this study, we report on the effects of antagonists of the NPY-2 receptor (Y2R) in comparison with empagliflozin and semaglutide, substances that are known to be beneficial in MASLD. (2) Methods: Diet-induced obese (DIO) male Wistar rats were randomized into the following treatment groups: empagliflozin, semaglutide ± PYY, the Y2R antagonists JNJ 31020028 and a food-restricted group, as well as a control group. After a treatment period of 8 weeks, livers were weighed and histologically evaluated. QrtPCR was performed to investigate liver inflammation and de novo lipogenesis (in liver and adipose tissue). Serum samples were analysed for metabolic parameters. (3) Results: Semaglutide + PYY led to significant weight loss, reduced liver steatosis ( = 0.05), and decreased inflammation, insulin resistance, and leptin levels. JNJ-31020028 prevented steatosis ( = 0.03) without significant weight loss. Hepatic downregulation of de novo lipogenesis-regulating genes (SREBP1 and MLXIPL) was observed in JNJ-31020028-treated rats ( ≤ 0.0001). Food restriction also resulted in significantly reduced weight, steatosis, and hepatic de novo lipogenesis. (4) Conclusions: Body weight reduction (e.g., by food restriction or drugs like semaglutide ± PYY) is effective in improving liver steatosis in DIO rats. Remarkably, the body-weight-neutral Y2R antagonists may be effective in preventing liver steatosis through a reduction in de novo lipogenesis, making this drug class a candidate for the treatment of (early) MASLD.
（1）背景：神经肽 Y（NPY）系统调节剂参与能量代谢，但 NPY 受体拮抗剂对代谢功能障碍相关脂肪性肝病（MASLD）的影响在很大程度上尚不清楚，MASLD 是一种常见的肥胖相关并发症。在这项研究中，我们报告了 NPY-2 受体（Y2R）拮抗剂的作用，与已知对 MASLD 有益的恩格列净和司美格鲁肽进行了比较。（2）方法：将饮食诱导肥胖（DIO）雄性 Wistar 大鼠随机分为以下治疗组：恩格列净、司美格鲁肽+PYY、Y2R 拮抗剂 JNJ 31020028 和限食组以及对照组。治疗 8 周后，称取肝脏重量并进行组织学评估。进行 QrtPCR 以研究肝脏炎症和从头脂肪生成（在肝脏和脂肪组织中）。分析血清样本以评估代谢参数。（3）结果：司美格鲁肽+PYY 导致显著的体重减轻，减少肝脂肪变性（=0.05），并降低炎症、胰岛素抵抗和瘦素水平。JNJ-31020028 可预防脂肪变性（=0.03），而不显著减轻体重。在 JNJ-31020028 治疗的大鼠中观察到肝脏中与从头脂肪生成调节基因（SREBP1 和 MLXIPL）的下调（≤0.0001）。限食也导致体重、脂肪变性和肝脏从头脂肪生成显著减少。（4）结论：体重减轻（例如通过限食或司美格鲁肽+PYY 等药物）可有效改善 DIO 大鼠的肝脂肪变性。值得注意的是，体重中性的 Y2R 拮抗剂可能通过减少从头脂肪生成而有效预防肝脂肪变性，使这类药物成为（早期）MASLD 治疗的候选药物。
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