Melanocortin-independent Effects of Leptin on Hepatic Glucose Fluxes

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 gluconeog...

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Bibliographic Details
Published in:The Journal of biological chemistry 2004-11, Vol.279 (48), p.49704-49715
Main Authors: Gutiérrez-Juárez, Roger, Obici, Silvana, Rossetti, Luciano
Format: Article
Language:English
Subjects:
Animals
Gluconeogenesis - physiology
Glucose - metabolism
Leptin - metabolism
Liver - metabolism
Male
Melanocyte-Stimulating Hormones - metabolism
Rats
Rats, Sprague-Dawley
Receptors, Melanocortin - metabolism
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Summary: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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M408665200