Melanocortin-independent Effects of Leptin on Hepatic Glucose Fluxes

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.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). Leptin regulates food intake and body adiposity partly via activation of melanocortin receptors in the hypothalamus and in other areas within the central nervous system (2, 3). It is now well recognized that leptin also plays an important role in the regulation of insulin action and intermediate metabolism (4 -9). Indeed, prolonged administration of recombinant leptin to nondiabetic and diabetic rats (10 -13) as well as to lipodystrophic humans and mice (4, 14) markedly improves in vivo insulin action. Similarly, bi-directional modulation of the activity of the central melanocortin pathway leads to significant changes in hepatic and peripheral insulin action (15). On the other hand, the prolonged administration of either leptin or melanocortin agonists or antagonists also impacts on the distribution of body adiposity and on lipid homeostasis (10, 15-18). These effects are in turn likely to secondarily influence the in vivo action of insulin on metabolic parameters (15). Thus, 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). This effect is seen following either systemic or central administration of the hor...

Hypothalamic control of glucose and lipid metabolism in skeletal muscle

“…In contrast, under physiological conditions with high insulin levels, which are usually accompanied by high blood glucose concentrations, leptin enhances the insulin-induced suppression of glucose production and accumulation of glycogen in the liver. The reciprocal effect of leptin on glucose metabolism in the liver is also supported by a previous study showing that an icv injection of leptin regulates gluconeogenesis and glycogenolysis in the liver through distinct mechanisms in the brain 28) . Leptin has been shown to inhibit expression of gluconeogenic genes in the liver, while it stimulates glycogenolysis in the tissue under a normal insulin level.…”

Brain Adipocytokine Action and Metabolic Regulation

“…Short-term voluntary overfeeding induces resistance to the effects of systemic insulin and leptin on liver glucose metabolism (71). Leptin administered intracerebroventricularly restores insulin sensitivity by inhibiting glucose production mainly by decreasing glycogenolysis (70). Together, these studies establish critical roles of leptin and MC4 receptor in glucose regulation that could be harnessed for treatment of diabetes.…”

“…This result supports an early action of leptin on hepatic glucose metabolism. In rat, intracerebroventricular leptin infusion stimulates gluconeogenesis but does not affect glucose production, as a result of a compensatory decrease in glycogenolysis (70). Pharmacological blockade of melanocortin prevents leptin's ability to stimulate gluconeogenesis; however, inhibition of glucose production and glycogenolysis is independent of melanocortin signaling (70).…”

Contrôle de la glycémie par l’axe nerveux intestin-cerveau

“…Les neurones du noyau arqué expriment de multiples récepteurs d'hormones. La leptine [4], mais aussi l'insuline et les métabolites tels que le glucose ou les acides gras [1], ont directement accès au noyau arqué au niveau de l'éminence médiane [31].…”

“…La découverte de la leptine, une hormone sécrétée par le tissu adipeux, qui diminue la sensation de faim en se liant à des récepteurs présents dans l'hypothalamus, en est une parfaite illustration. La leptine est en effet capable également de réguler la production endogène de glucose par des mécanismes dépendants et indépendants de l'hypothalamus [3,4]. L'hypothalamus et le tronc cérébral, où se connectent la moelle épinière et le système nerveux périphérique (nerfs vagues), occupent une place centrale dans ces régulations [5].…”