Effects of antagonists of the NPY-2 receptor, semaglutide, PYY3-36, and empagliflozin on metabolic dysfunction-associated steatotic liver disease in diet-induced obese rats

Simon Kloock; Niklas Haerting; Gloria Herzog; Marie Oertel; Niklas Geiger; Andreas Geier; Alexander Nickel; Kohlhaas Michael; Martin Fassnacht; Ulrich Dischinger

doi:10.1530/endoabs.99.RC12.5

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Endocrine Abstracts (2024) 99 RC12.5 | DOI: 10.1530/endoabs.99.RC12.5

ECE2024 Rapid Communications Rapid Communications 12: Diabetes, Obesity, Metabolism and Nutrition | Part II (5 abstracts)

Effects of antagonists of the NPY-2 receptor, semaglutide, PYY3-36, and empagliflozin on metabolic dysfunction-associated steatotic liver disease in diet-induced obese rats

Simon Kloock ¹ , Niklas Haerting ¹ , Gloria Herzog ² , Marie Oertel ¹ , Niklas Geiger ¹ , Andreas Geier ³ , Alexander Nickel ⁴ , Kohlhaas Michael ⁴ , Martin Fassnacht ¹ & Ulrich Dischinger ^1,4

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¹Center for Internal Medicine at the University of Würzburg ZIM, Endocrinology and Diabetes, Würzburg, Germany; ²Institute of Pathology at the University of Würzburg, Würzburg, Germany; ³Center for Internal Medicine at the University of Würzburg ZIM, Hepatology, Würzburg, Germany; ⁴Comprehensive Heart Failure Center, Cardiology, Würzburg, Germany

Metabolic dysfunction-associated steatotic liver disease (MASLD) frequently accompanies obesity, posing a significant health concern. The Neuropeptide Y (NPY) system, a key player in energy metabolism regulation, has implications for liver health, yet the impact of NPY receptor antagonists remains largely unexplored. This study investigates the effects of antagonists targeting the NPY-2 receptor (Y2R) in comparison to known MASLD-beneficial substances.

Methods: Diet-induced obese (DIO) male Wistar rats were divided into the following treatment groups: empagliflozin, semaglutide, semaglutide ±PYY3-36, Y2R antagonist JNJ-31020028, a food-restricted group, and a control group. After 8 weeks of treatment, livers were assessed for weight and histology. QrtPCR was utilized to examine liver inflammation and de novo lipogenesis in both liver and adipose tissue. Serum samples were analyzed for metabolic parameters.

Results: The combination of semaglutide and PYY3-36 resulted in weight loss, significantly reducing liver steatosis compared to controls (p = 0.05). Markers of inflammation, insulin resistance, and leptin levels were also reduced. Empagliflozin exhibited limited impact on the measured parameters. JNJ-31020028 did not induce significant weight loss but prevented steatosis (P=0.03), with no effect on inflammation. The de novo lipogenesis regulating genes SREBP1 and MLXIPL were downregulated in livers of JNJ-31020028 treated DIO rats compared to controls (p ≤ 0.0001), with no observed effect in visceral adipose tissue. Food restriction led to significant reductions in weight, steatosis, and de novo lipogenesis.

Discussion: Body weight reduction, achieved through methods like food restriction or drmgs such as semaglutide ±PYY3-36, proved effective in ameliorating liver steatosis in DIO rats. Notably, the weight-neutral Y2R antagonists showed promise in preventing liver steatosis through a reduction in de novo lipogenesis. Further investigations are needed to elucidate the molecular impact of the NPY system on liver pathophysiology.