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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 \u00b1 PYY3-36, 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 + PYY3-36 led to significant weight loss, reduced liver steatosis (p = 0.05), and decreased inflammation, insulin resistance, and leptin levels. JNJ-31020028 prevented steatosis (p = 0.03) without significant weight loss. Hepatic downregulation of de novo lipogenesis-regulating genes (SREBP1 and MLXIPL) was observed in JNJ-31020028-treated rats (p \u2264 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 \u00b1 PYY3-36) 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.<\/jats:p>","DOI":"10.3390\/nu16060904","type":"journal-article","created":{"date-parts":[[2024,3,21]],"date-time":"2024-03-21T06:35:30Z","timestamp":1711002930000},"page":"904","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Effects of NPY-2 Receptor Antagonists, Semaglutide, PYY3-36, and Empagliflozin on Early MASLD in Diet-Induced Obese Rats"],"prefix":"10.3390","volume":"16","author":[{"given":"Simon","family":"Kloock","sequence":"first","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology and Diabetes, University Hospital Wuerzburg, University of Wuerzburg, 97080 Wuerzburg, Germany"}]},{"given":"Niklas","family":"Haerting","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology and Diabetes, University Hospital Wuerzburg, University of Wuerzburg, 97080 Wuerzburg, Germany"}]},{"given":"Gloria","family":"Herzog","sequence":"additional","affiliation":[{"name":"Institute of Pathology, University of Wuerzburg, 97070 Wuerzburg, Germany"}]},{"given":"Marie","family":"Oertel","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology and Diabetes, University Hospital Wuerzburg, University of Wuerzburg, 97080 Wuerzburg, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2163-8422","authenticated-orcid":false,"given":"Niklas","family":"Geiger","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology and Diabetes, University Hospital Wuerzburg, University of Wuerzburg, 97080 Wuerzburg, Germany"}]},{"given":"Andreas","family":"Geier","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Hepatology, University Hospital Wuerzburg, University of Wuerzburg, 97080 Wuerzburg, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9192-7674","authenticated-orcid":false,"given":"Vasco","family":"Sequeira","sequence":"additional","affiliation":[{"name":"Comprehensive Heart Failure Center, University Hospital Wuerzburg, University of Wuerzburg, 97080 Wuerzburg, Germany"}]},{"given":"Alexander","family":"Nickel","sequence":"additional","affiliation":[{"name":"Comprehensive Heart Failure Center, University Hospital Wuerzburg, University of Wuerzburg, 97080 Wuerzburg, Germany"}]},{"given":"Michael","family":"Kohlhaas","sequence":"additional","affiliation":[{"name":"Comprehensive Heart Failure Center, University Hospital Wuerzburg, University of Wuerzburg, 97080 Wuerzburg, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6170-6398","authenticated-orcid":false,"given":"Martin","family":"Fassnacht","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology and Diabetes, University Hospital Wuerzburg, University of Wuerzburg, 97080 Wuerzburg, Germany"}]},{"given":"Ulrich","family":"Dischinger","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Endocrinology and Diabetes, University Hospital Wuerzburg, University of Wuerzburg, 97080 Wuerzburg, Germany"},{"name":"Comprehensive Heart Failure Center, University Hospital Wuerzburg, University of Wuerzburg, 97080 Wuerzburg, Germany"}]}],"member":"1968","published-online":{"date-parts":[[2024,3,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1016\/j.jhep.2021.05.022","article-title":"Burden of non-alcoholic fatty liver disease in Asia, the Middle East and North Africa: Data from Global Burden of Disease 2009\u20132019","volume":"75","author":"Golabi","year":"2021","journal-title":"J. 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