SHORT-TERM EFFECTS OF LEPTIN ON HEPATIC GLUCONEOGENESIS AND IN-VIVO INSULIN ACTION

Long term administration of leptin decreases caloric intake and fat ma ss and improves glucose tolerance. Here we examine whether leptin acut ely regulates peripheral and hepatic insulin action. Recombinant mouse leptin (0.3 mg/kg.h, Leptin +) or vehicle (Leptin -) were administere d for 6 h to 4-month-old rats (n = 20), and insulin (3 milliunits/kg.m in) clamp studies were performed. During physiologic hyperinsulinemia (plasma insulin similar to 65 microunits/ml), the rates of whole body glucose uptake, glycolysis, and glycogen synthesis and the rates of 2- deoxyglucose uptake in individual tissues were similar in Leptin - and Leptin +. Post-absorptive hepatic glucose production (HGP) was simila r in the two groups. However, leptin enhanced insulin's inhibition of HGP (4.1 +/- 0.7 and 6.2 +/- 0.7 mg/kg.min; p < 0.05). The decreased H GP in the Leptin + group was due to a marked suppression of hepatic gl ycogenolysis (0.7 +/- 0.1 versus 4.1 +/- 0.6 mg/kg.min, in Leptin + ve rsus Leptin -, respectively; p < 0.001), whereas the % contribution of gluconeogenesis to HGP was markedly increased (82 +/- 3% versus 36 +/ - 4% in Leptin + and Leptin -, respectively; p < 0.001). At the end of the 6-h leptin infusion, the hepatic abundance of glucokinase mRNA wa s decreased, whereas that of phosphoenolpyruvate carboxykinase mRNA wa s increased compared with Leptin -. We conclude that an acute increase in plasma leptin 1) enhances insulin's ability to inhibit HGP, 2) doe s not affect peripheral insulin action, and 3) induces a redistributio n of intrahepatic glucose fluxes and changes in the gene expression of hepatic enzymes that closely resemble those of fasting.