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J Biol Chem, Vol. 273, Issue 47, 31160-31167, November 20, 1998
From the Diabetes Research and Training Center and Division of
Endocrinology, Albert Einstein College of Medicine,
Bronx, New York 10461
Acute intravenous infusions of leptin markedly
alter hepatic glucose fluxes (Rossetti, L., Massillon, D., Barzilai,
N., Vuguin, P., Chen, W., Hawkins, M., Wu, J., and Wang, J. (1997)
J. Biol. Chem. 272, 27758-22763). Here we examine
whether intracerebroventricular (ICV) leptin administration regulates
peripheral and hepatic insulin action. Recombinant mouse leptin
(n = 14; 0.02 or 1 µg/kg·h) or vehicle
(n = 9) were administered ICV for 6 h to
conscious rats, and insulin action was determined by insulin (3 milliunits/kg·min) clamp and tracer dilution techniques. During
physiologic hyperinsulinemia (~65 microunits/ml), the rates of
glucose uptake (Rd, 20.1 ± 0.6 and 23.1 ± 0.7 versus 21.7 ± 0.6 mg/kg·min;
p = NS), glycolysis and glycogen synthesis were
similar in rats receiving low- and high-dose leptin versus
vehicle. ICV leptin resulted in a 2-3-fold increase in hepatic
phosphoenolpyruvate carboxykinase mRNA levels. Glycogenolysis and
PEP-gluconeogenesis (2.1 ± 0.3 mg/kg·min) contributed similarly
to endogenous glucose production (GP) in the vehicle-infused group.
However, gluconeogenesis accounted for ~80% of GP in both groups
receiving ICV leptin, while hepatic glycogenolysis was markedly
suppressed (0.7 ± 0.3 and 1.2 ± 0.3 versus
2.2 ± 0.4 mg/kg·min, in rats receiving low- and high-dose leptin versus vehicle, respectively; p < 0.01). In summary, short-term ICV leptin administration: 1) failed to
affect peripheral insulin action, but 2) induced a striking
re-distribution of intrahepatic glucose fluxes. The latter effect
largely reproduced that of leptin given systemically at much higher
doses. Thus, the regulation of hepatic glucose fluxes by leptin is
largely mediated via its central receptors.
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