Melanocortin-independent Effects of Leptin on Hepatic Glucose Fluxes

Roger Gutiérrez-Juárez,Silvana Obici,Luciano Rossetti

doi:10.1074/jbc.m408665200

Roger Gutiérrez-Juárez, Silvana Obici + Show 1 more

Open Access

https://doi.org/10.1074/jbc.m408665200

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Abstract

Leptin and insulin share some hypothalamic signaling molecules, but their central administration induces different effects on hepatic glucose fluxes. Acute insulin infusion in the third cerebral ventricle inhibits endogenous glucose production (GP), whereas acute leptin infusion stimulates gluconeogenesis but does not alter GP because of a compensatory decrease in glycogenolysis. Because melanocortin agonists also stimulate hepatic gluconeogenesis, here we examined whether central melanocortin blockade modifies the acute effects of leptin on GP, on gluconeogenesis, on glycogenolysis, and/or on the hepatic expression of the gluconeogenic enzymes glucose-6-phosphatase (Glc-6-Pase) and phosphoenolpyruvate carboxykinase (PEPCK). Systemic or central administration of leptin alone did not alter GP, despite increasing both the rate of gluconeogenesis and the expression of Glc-6-Pase and PEPCK. When activation of the central melanocortin pathway was prevented, the effects of leptin on gluconeogenesis, Glc-6-Pase, and PEPCK were abolished, and a marked suppression of glycogenolysis resulted in decreased GP. We conclude that leptin regulates hepatic glucose fluxes through a melanocortin-dependent pathway leading to stimulation of gluconeogenesis and a melanocortin-independent pathway causing inhibition of GP and glycogenolysis.

Highlights

Leptin, the 167-amino acid polypeptide product of the ob gene, is secreted by the adipose tissue and acts mainly on the central nervous system to regulate energy balance [1]
Because melanocortin agonists stimulate hepatic gluconeogenesis, here we examined whether central melanocortin blockade modifies the acute effects of leptin on glucose production (GP), on gluconeogenesis, on glycogenolysis, and/or on the hepatic expression of the gluconeogenic enzymes glucose-6-phosphatase (Glc-6-Pase) and phosphoenolpyruvate carboxykinase (PEPCK)
To delineate the contribution of the central melanocortin pathway to the acute effects of leptin on glucose homeostasis, we first examined whether and how the central activation of the melanocortin pathway modulates glucose fluxes, and we examined the contribution of the central melanocortin pathway to the acute effects of systemic and ICV leptin on glucose kinetics

Summary

Introduction

The 167-amino acid polypeptide product of the ob gene, is secreted by the adipose tissue and acts mainly on the central nervous system to regulate energy balance [1]. Hand, the prolonged administration of either leptin or melanocortin agonists or antagonists impacts on the distribution of body adiposity and on lipid homeostasis [10, 15,16,17,18] These effects are in turn likely to secondarily influence the in vivo action of insulin on metabolic parameters [15]. It is important to delineate the acute effects of leptin and melanocortins on metabolic fluxes prior to the onset of changes in energy balance, body composition, and lipid storage In this regard, acute administration of leptin to postabsorptive rats causes a marked redistribution of intrahepatic glucose fluxes, with a marked increase in the relative contribution of gluconeogenesis and a parallel decrease in the contribution of glycogenolysis to hepatic glucose output [5, 6]. Our results reveal specific and potent melanocortindependent and melanocortin-independent effects of leptin on hepatic glucose fluxes

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