2500-P: Interleukin-1β Shifts Hepatic Metabolism toward Lipid Accumulation

Introduction and Objective: Obesity and type 2 diabetes are associated with increased activation of the inflammasome-IL-1β pathway. Despite extensive evidence for its role in chronic metabolic inflammation, little attention has been paid to the potential acute physiological functions of IL-1β in metabolic regulation. Recently, we demonstrated that acute IL-1β stimulation enhances insulin secretion. In the present study, we investigated whether IL-1β exerts additional insulin independent metabolic effects, with a particular focus on hepatic metabolism. Methods: Fasting wild-type and hepatocyte-specific IL-1 receptor knockout mice received IL-1β. Primary hepatocytes from wild-type and IL-1 receptor-deficient mice were stimulated with IL-1β, and glucose production, hepatocyte function as well as gene and protein expression were assessed. Results: In vivo, pre-treatment with IL-1β acutely enhanced insulin secretion followed by sustained hypoglycemia, despite normalization of circulating insulin, due to suppressed hepatic glucose production. Furthermore, IL-1β promoted triglyceride accumulation in the liver and also activated and expanded neutrophils inducing a metabolic shift toward glycolysis. In vitro, IL-1β inhibited glucagon-stimulated gluconeogenesis and suppressed key gluconeogenic enzymes, redirecting hepatocyte metabolism toward lipid synthesis in an IL-1 receptor-dependent manner. Conclusion: IL-1β suppresses hepatic glucose output by inhibiting gluconeogenesis while promoting lipid synthesis. This novel immune-metabolic effect limit systemic glucose availability and provides an explanation for hypoglycemia observed during severe inflammation. Chronically, the increased IL-1β activity observed during obesity, may reprogram hepatic glucose metabolism, thereby contributing to hepatic lipid accumulation and the development of MASH. These findings provide a rational for blocking the inflammasome-IL-1β axis to prevent inflammatory liver disease. Disclosure P. Neubert: None. K.A. Trimigliozzi: None. D.T. Meier: None. M. Donath: Advisory Panel; Ended; Novo Nordisk, Lilly. Board Member; Current; Olatec.