Acrp30, an adipose-derived protein, inhibits endogenous glucose production in mice. When infused, it lowers glucose levels by reducing hepatic glucose production without affecting peripheral glucose uptake, glycolysis, or glycogen synthesis. This effect is primarily due to a 65% reduction in glucose production, which is linked to decreased expression of gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in the liver. Acrp30 also increases the activity of the direct pathway of glucose-6-phosphate biosynthesis, indicating enhanced hepatic glucose phosphorylation. These findings suggest that Acrp30 modulates hepatic glucose metabolism by inhibiting gluconeogenesis and reducing glucose production. The study used pancreatic insulin clamps in conscious mice to assess the effects of Acrp30 on glucose metabolism. The results indicate that Acrp30's acute hypoglycemic effect is mainly due to its ability to suppress hepatic glucose production, rather than enhancing glucose uptake. The study also highlights the potential role of Acrp30 in glucose homeostasis and its possible involvement in the regulation of insulin sensitivity. The findings contribute to the understanding of the molecular mechanisms underlying insulin resistance and the role of adipose-derived proteins in metabolic regulation.Acrp30, an adipose-derived protein, inhibits endogenous glucose production in mice. When infused, it lowers glucose levels by reducing hepatic glucose production without affecting peripheral glucose uptake, glycolysis, or glycogen synthesis. This effect is primarily due to a 65% reduction in glucose production, which is linked to decreased expression of gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) in the liver. Acrp30 also increases the activity of the direct pathway of glucose-6-phosphate biosynthesis, indicating enhanced hepatic glucose phosphorylation. These findings suggest that Acrp30 modulates hepatic glucose metabolism by inhibiting gluconeogenesis and reducing glucose production. The study used pancreatic insulin clamps in conscious mice to assess the effects of Acrp30 on glucose metabolism. The results indicate that Acrp30's acute hypoglycemic effect is mainly due to its ability to suppress hepatic glucose production, rather than enhancing glucose uptake. The study also highlights the potential role of Acrp30 in glucose homeostasis and its possible involvement in the regulation of insulin sensitivity. The findings contribute to the understanding of the molecular mechanisms underlying insulin resistance and the role of adipose-derived proteins in metabolic regulation.