2489-P: Hepatic NgBR Is Essential for KAT7-Dependent Adiponectin Receptor Regulation and Adiponectin Sensitivity

Introduction and Objective: Adiponectin is a critical regulator of hepatic glucose and lipid metabolism, yet the mechanisms governing adiponectin receptor responsiveness in metabolic disease remain poorly defined. The Nogo-B receptor (NgBR/NUS1) has been implicated in metabolic regulation, but its role in hepatic adiponectin sensitivity is unknown. This study aimed to determine whether NgBR controls adiponectin receptor competence and downstream metabolic signaling in the liver. Methods: Hepatic NgBR expression was analyzed using integrated transcriptomic datasets from humans, cynomolgus monkeys, and mouse models of obesity and type 2 diabetes. Hepatocyte-specific NgBR knockout (NgBR HepKO) mice and AAV-mediated NgBR rescue models were used to assess adiponectin responsiveness in vivo. Metabolic analyses included glucose tolerance, hepatic gluconeogenic gene expression, ceramide profiling, and AMPK activation following treatment with the adiponectin agonist AdipoRon. Chromatin immunoprecipitation assays evaluated histone acetylation and KAT7 occupancy at adiponectin receptor promoters. Results: Hepatic NgBR expression was consistently reduced in obesity and type 2 diabetes across species and positively correlated with AdipoR2, the predominant adiponectin receptor in hepatocytes. NgBR HepKO mice exhibited blunted transcriptional and physiological responses to AdipoRon, characterized by impaired AMPK phosphorylation, persistent gluconeogenesis, and hepatic ceramide accumulation. Mechanistically, NgBR deficiency reduced KAT7 expression and activating histone acetylation (H3K14 and H4K5) at AdipoR1 and AdipoR2 promoters, leading to diminished receptor expression. AAV-mediated restoration of NgBR reinstated adiponectin sensitivity, AMPK activation, lipid remodeling, and glucose homeostasis. Conclusion: NgBR is a central hepatic determinant of adiponectin receptor functionality and defines an NgBR-KAT7 epigenetic axis underlying hepatic adiponectin resistance in metabolic disease. Disclosure M. Mohiuddin: None. M.B. Tirumalasetty: None. R. Barua: None. M. Wahiduzzaman: None. M. Choubey: None. Q.R. Miao: None. Funding National Institutes of Health (DK132056)