Intracerebroventricular leptin regulates hepatic but not peripheral glucose fluxes

Li Sen Liu, George B. Karkanias, Jose' C. Morales, Meredith Hawkins, Nir Barzilai, Jiali Wang, Luciano Rossetti

Research output: Contribution to journalArticle

178 Scopus citations

Abstract

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 (R(d), 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.

Original languageEnglish (US)
Pages (from-to)31160-31167
Number of pages8
JournalJournal of Biological Chemistry
Volume273
Issue number47
DOIs
StatePublished - Nov 20 1998

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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