Endogenous glucose production is inhibited by the adipose-derived protein Acrp30

Abstract

Intraperitoneal injection of purified recombinant Acrp30 lowers glucose levels in mice. To gain insight into the mechanism(s) of this hypoglycemic effect, purified recombinant Acrp30 was infused in conscious mice during a pancreatic euglycemic clamp. In the presence of physiological hyperinsulinemia, this treatment increased circulating Acrp30 levels by approximately twofold and stimulated glucose metabolism. The effect of Acrp30 on in vivo insulin action was completely accounted for by a 65% reduction in the rate of glucose production. Similarly, glucose flux through glucose-6-phosphatase (G6Pase) decreased with Acrp30, whereas the activity of the direct pathway of glucose-6-phosphate biosynthesis, an index of hepatic glucose phosphorylation, increased significantly. Acrp30 did not affect the rates of glucose uptake, glycolysis, or glycogen synthesis. These results indicate that an acute increase in circulating Acrp30 levels lowers hepatic glucose production without affecting peripheral glucose uptake. Hepatic expression of the gluconeogenic enzymes phosphoenolpyruvate carboxykinase and G6Pase mRNAs was reduced by more than 50% following Acrp30 infusion compared with vehicle infusion. Thus, a moderate rise in circulating levels of the adipose-derived protein Acrp30 inhibits both the expression of hepatic gluconeogenic enzymes and the rate of endogenous glucose production.

Figure 1

(a) Time course of plasma Acrp30 during euglycemic clamps. Representative Western blot analysis of plasma from an Acrp30-infused mouse. An affinity-purified, ¹²⁵I-labeled rabbit anti-mouse Acrp30 antibody was used. A single band was recognized at 30 kDa that was increased by approximately twofold (P < 0.001) from baseline (time = 0). (b) Effect of Acrp30 on the rate of glucose infusion. (c) Effect of Acrp30 on the rates of glucose disappearance (Rd), glycolysis, and glycogen synthesis. All measurements were obtained while plasma glucose concentration was maintained at approximately 6 mM under steady-state conditions. *P < 0.05 vs. vehicle.

Figure 2

(a) Effect of Acrp30 on the rates of glucose production, G6Pase flux, and glucose cycling. The measurements were obtained while plasma glucose concentration was maintained at approximately 6 mM under steady-state conditions. (b) Effect of Acrp30 on hepatic mRNA expression of PEPCK. (c) Effect of Acrp30 on G6Pase. (d) Representative Northern blots of liver samples from Acrp30-infused (first three lanes) and vehicle-infused (last three lanes) mice.