Intracerebroventricular Leptin Regulates Hepatic but Not Peripheral Glucose Fluxes

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

doi:10.1074/jbc.273.47.31160

Lisen Liu, George B Karkanias + Show 5 more

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https://doi.org/10.1074/jbc.273.47.31160

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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 microgram/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 (approximately 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 approximately 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.

Highlights

Leptin, the protein encoded by the ob gene, is an anorectic hormone secreted by adipose cells [1,2,3,4,5,6]
This study demonstrates that an acute ICV infusion of recombinant leptin antagonizes the action of insulin on the gene expression of phosphoenolpyruvate carboxykinase (PEPCK) in the liver and results in marked changes in the intrahepatic partitioning of glucose fluxes with increased gluconeogenesis and decreased glycogenolysis (Fig. 7)
It is likely that these metabolic effects of leptin participate to the regulation of hepatic glucose metabolism under physiologic conditions

Summary

Introduction

The protein encoded by the ob gene, is an anorectic hormone secreted by adipose cells [1,2,3,4,5,6]. Nutritional and hormonal factors can regulate ob gene expression in adipose cells and leptin levels in plasma [3, 13, 14, 16, 17]. We have recently demonstrated that marked and acute elevations in the plasma leptin concentrations modulate the hepatic gene expression of the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) and the rate of gluconeogenesis [22]. It is presently unknown whether the latter metabolic effects of leptin are, at least in part, mediated through its action on hypothalamic receptors. As recent studies have suggested that a highly selective ␤3-adrenergic receptor agonist (CL 316,243) exerts potent “leptin-like” effects in the hypothalamic regulation of food intake [5], its metabolic effects were examined

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