NgBR controls hepatic adiponectin signaling competence through KAT7-dependent chromatin regulation.

Adiponectin signaling is essential for hepatic glucose homeostasis, yet the molecular basis of adiponectin receptor responsiveness remains incompletely understood. Here, we identify the Nogo-B receptor (NgBR; NUS1) as a regulator of hepatic adiponectin sensitivity. Across human, cynomolgus monkey, and mouse datasets, hepatic NgBR expression is consistently reduced in obesity-associated diabetes, indicating a conserved metabolic signature. Hepatocyte-specific NgBR deletion abolishes the metabolic effects of the adiponectin agonist AdipoRon, resulting in impaired AMPK activation, persistent gluconeogenesis, and ceramide accumulation. Mechanistically, NgBR loss suppresses KAT7 expression and reduces histone acetylation at AdipoR1 and AdipoR2 promoters, thereby limiting receptor expression. Adeno-associated virus (AAV)-mediated restoration of hepatic NgBR reinstates KAT7-dependent chromatin activation, adiponectin receptor expression, and glucose homeostasis. These findings support a hepatocellular mechanism in which NgBR maintains adiponectin receptor competence and suggest a potential therapeutic strategy for restoring adiponectin responsiveness in metabolic disease.