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 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 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 (1Friedman J.M. Halaas J.L. Nature. 1998; 395: 763-770Crossref PubMed Scopus (4580) Google Scholar). 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 (2Seeley R.J. Yagaloff K.A. Fisher S.L. Burn P. Thiele T.E. van Dijk G. Baskin D.G. Schwartz M.W. Nature. 1997; 390: 349Crossref PubMed Scopus (399) Google Scholar, 3Balthasar N. Coppari R. McMinn J. Liu S.M. Lee C.E. Tang V. Kenny C.D. McGovern R.A. Chua Jr., S.C. Elmquist J.K. Lowell B.B. Neuron. 2004; 42: 983-991Abstract Full Text Full Text PDF PubMed Scopus (740) Google Scholar). It is now well recognized that leptin also plays an important role in the regulation of insulin action and intermediate metabolism (4Shimomura I. Hammer R.E. Ikemoto S. Brown M.S. Goldstein J.L. Nature. 1999; 401: 73-76Crossref PubMed Scopus (873) Google Scholar, 5Rossetti L. Massillon D. Barzilai N. Vuguin P. Chen W. Hawkins M. Wu J. Wang J. J. Biol. Chem. 1997; 272: 27758-27763Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar, 6Liu L. Karkanias G.B. Morales J.C. Hawkins M. Barzilai N. Wang J. Rossetti L. J. Biol. Chem. 1998; 273: 31160-31167Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar, 7Shimabukuro M. Koyama K. Chen G. Wang M.Y. Trieu F. Lee Y. Newgard C.B. Unger R.H. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 4637-4641Crossref PubMed Scopus (623) Google Scholar, 8Bai Y. Zhang S. Kim K.S. Lee J.K. Kim K.H. J. Biol. Chem. 1996; 271: 13939-13942Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar, 9Lord G.M. Matarese G. Howard J.K. Baker R.J. Bloom S.R. Lechler R.I. Nature. 1998; 394: 897-901Crossref PubMed Scopus (1865) Google Scholar). Indeed, prolonged administration of recombinant leptin to non-diabetic and diabetic rats (10Barzilai N. Wang J. Massilon D. Vuguin P. Hawkins M. Rossetti L. J. Clin. Invest. 1997; 100: 3105-3110Crossref PubMed Scopus (297) Google Scholar, 11Chinookoswong N. Wang J.L. Shi Z.Q. Diabetes. 1999; 48: 1487-1492Crossref PubMed Scopus (164) Google Scholar, 12Yaspelkis B.B. II I Davis J.R. Saberi M. Smith T.L. Jazayeri R. Singh M. Fernandez V. Trevino B. Chinookoswong N. Wang J. Shi Z.Q. Levin N. Am. J. Physiol. 2001; 280: E130-E142PubMed Google Scholar, 13Hidaka S. Yoshimatsu H. Kondou S. Tsuruta Y. Oka K. Noguchi H. Okamoto K. Sakino H. Teshima Y. Okeda T. Sakata T. FASEB J. 2002; 16: 509-518Crossref PubMed Scopus (90) Google Scholar) as well as to lipodystrophic humans and mice (4Shimomura I. Hammer R.E. Ikemoto S. Brown M.S. Goldstein J.L. Nature. 1999; 401: 73-76Crossref PubMed Scopus (873) Google Scholar, 14Petersen K.F. Oral E.A. Dufour S. Befroy D. Ariyan C. Yu C. Cline G.W. DePaoli A.M. Taylor S.I. Gorden P. Shulman G.I. J. Clin. Invest. 2002; 109: 1345-1350Crossref PubMed Scopus (640) Google Scholar) 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 (15Obici S. Feng Z. Tan J. Liu L. Karkanias G. Rossetti L. J. Clin. Invest. 2001; 108: 1079-1085Crossref PubMed Scopus (324) Google Scholar). 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 (10Barzilai N. Wang J. Massilon D. Vuguin P. Hawkins M. Rossetti L. J. Clin. Invest. 1997; 100: 3105-3110Crossref PubMed Scopus (297) Google Scholar, 15Obici S. Feng Z. Tan J. Liu L. Karkanias G. Rossetti L. J. Clin. Invest. 2001; 108: 1079-1085Crossref PubMed Scopus (324) Google Scholar, 16Barzilai N. She L. Liu L. Wang J. Hu M. Vuguin P. Rossetti L. Am. J. Physiol. 1999; 277: E291-E298PubMed Google Scholar, 17Pierroz D.D. Ziotopoulou M. Ungsunan L. Moschos S. Flier J.S. Mantzoros C.S. Diabetes. 2002; 51: 1337-1345Crossref PubMed Scopus (172) Google Scholar, 18Bluher S. Ziotopoulou M. Bullen Jr., J.W. Moschos S.J. Ungsunan L. Kokkotou Mantzoros C.S. Diabetes. 2004; PubMed Scopus Google Scholar). effects in to the in vivo action of insulin on (15Obici S. Feng Z. Tan J. Liu L. Karkanias G. Rossetti L. J. Clin. Invest. 2001; 108: 1079-1085Crossref PubMed Scopus (324) Google Scholar). is important to the acute effects of leptin and on fluxes to the of changes in energy body and lipid acute administration of leptin to rats a marked of glucose a marked in the of gluconeogenesis and a decrease in the of glycogenolysis to hepatic glucose L. Massillon D. Barzilai N. Vuguin P. Chen W. Hawkins M. Wu J. Wang J. J. Biol. Chem. 1997; 272: 27758-27763Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar, 6Liu L. Karkanias G.B. Morales J.C. Hawkins M. Barzilai N. Wang J. Rossetti L. J. Biol. Chem. 1998; 273: 31160-31167Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). is either or central administration of the L. Massillon D. Barzilai N. Vuguin P. Chen W. Hawkins M. Wu J. Wang J. J. Biol. Chem. 1997; 272: 27758-27763Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar, 6Liu L. Karkanias G.B. Morales J.C. Hawkins M. Barzilai N. Wang J. Rossetti L. J. Biol. Chem. 1998; 273: 31160-31167Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). the by leptin stimulates gluconeogenesis and inhibits Leptin to and via and partly central C. B.B. 2004; PubMed Scopus Google Scholar, Jr., 2004; PubMed Scopus Google Scholar). that leptin the hypothalamic melanocortin pathway and energy balance via and of GP, glucose Glc-6-Pase, phosphoenolpyruvate signaling and the and glucose homeostasis via signaling Jr., 2004; PubMed Scopus Google Scholar, M. Wang Y. Schwartz M.W. Jr., Nature. PubMed Scopus Google Scholar). leptin and insulin receptors to share of as the activation of Jr., Schwartz M.W. Nature. 2001; PubMed Scopus Google Scholar, C.D. R. Baskin D.G. Jr., R.J. Schwartz M.W. Diabetes. PubMed Scopus Google Scholar). because partly and partly D.G. R.J. S.C. Jr., D. Schwartz M.W. 1999; PubMed Scopus Google Scholar, S. D.D. Flier J.S. B.B. PubMed Scopus Google Scholar, S.C. R.J. S.C. 2002; PubMed Scopus Google Scholar). the acute administration of insulin markedly inhibits endogenous glucose production via a S. Zhang B.B. Karkanias G. Rossetti L. 2002; PubMed Scopus Google whereas the acute administration of leptin stimulates gluconeogenesis and PEPCK expression L. Massillon D. Barzilai N. Vuguin P. Chen W. Hawkins M. Wu J. Wang J. J. Biol. Chem. 1997; 272: 27758-27763Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar, 6Liu L. Karkanias G.B. Morales J.C. Hawkins M. Barzilai N. Wang J. Rossetti L. J. Biol. Chem. 1998; 273: 31160-31167Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). the of the central melanocortin pathway to the acute effects of leptin on glucose we examined whether and the central activation of the melanocortin pathway glucose and we examined the of the central melanocortin pathway to the acute effects of and leptin on glucose and melanocortin-dependent and melanocortin-independent effects of leptin on hepatic glucose fluxes. and rats were in and to a to the in vivo of the rats of by as L. Karkanias G.B. Morales J.C. Hawkins M. Barzilai N. Wang J. Rossetti L. J. Biol. Chem. 1998; 273: 31160-31167Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). the insulin the rats in the and as L. Massillon D. Barzilai N. Vuguin P. Chen W. Hawkins M. Wu J. Wang J. J. Biol. Chem. 1997; 272: 27758-27763Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar, 6Liu L. Karkanias G.B. Morales J.C. Hawkins M. Barzilai N. Wang J. Rossetti L. J. Biol. Chem. 1998; 273: 31160-31167Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). rats were a and were to of in vivo rats were as L. Karkanias G.B. Morales J.C. Hawkins M. Barzilai N. Wang J. Rossetti L. J. Biol. Chem. 1998; 273: 31160-31167Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). the the were the the of the in vivo leptin and leptin of the were in the or of a infusion of was and the of the glucose was the of the infusion and the of the the of and acid were the and the a infusion of of of the was and the of the of activity were the a insulin was and a infusion of insulin was and a infusion of glucose was and to the glucose rate of insulin infusion was to effects of the on was insulin to endogenous the of the in vivo the rats were body and tissue were in in of the tissue were of the and the and and in a was whereas the was leptin in was recombinant leptin of M. by and glucose was by the glucose insulin and leptin were by leptin was by acid were an by an to the of in was of and was to the of hepatic and glucose were by as A. Rossetti L. J. PubMed Scopus Google Scholar, A. Rossetti L. J. Clin. Invest. PubMed Scopus Google Scholar, L. A. Barzilai N. Howard K. G. Hu M. J. Clin. Invest. PubMed Scopus Google Scholar, L. Barzilai N. Chen W. T. D. C.E. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). were as (10Barzilai N. Wang J. Massilon D. Vuguin P. Hawkins M. Rossetti L. J. Clin. Invest. 1997; 100: 3105-3110Crossref PubMed Scopus (297) Google Scholar). the of the through glucose-6-phosphatase and glucose were as (10Barzilai N. Wang J. Massilon D. Vuguin P. Hawkins M. Rossetti L. J. Clin. Invest. 1997; 100: 3105-3110Crossref PubMed Scopus (297) Google Scholar). was the of hepatic to the activity of hepatic and hepatic the infusion of and on the gluconeogenesis Glc-6-Pase activity glycogenolysis was as the GP and of hepatic to the and the the of the and and in a and phosphoenolpyruvate carboxykinase expression was by was the to the was of the of in the was were also and were and was in a of I and a were in or expression was and and and and and was of the of was or of was and by the and of the of the by leptin regulates glucose of on energy balance and body we examined whether and acute modulation of the activity of central melanocortin receptors the action of leptin on hepatic and peripheral glucose fluxes. were in rats by L. Karkanias G.B. Morales J.C. Hawkins M. Barzilai N. Wang J. Rossetti L. J. Biol. Chem. 1998; 273: 31160-31167Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar). of the infusion were the of to a in examined whether stimulation of central melanocortin receptors insulin action on glucose of rats an infusion of either of the melanocortin of the melanocortin or both and W. R.A. Nature. 1997; PubMed Scopus Google Scholar) in insulin and were in the and the insulin the rate of glucose infusion to the glucose was decreased by and decrease was by the infusion of effects of insulin on glucose metabolism to stimulate the of glucose peripheral in and adipose and to the production of glucose by the rate of tissue glucose in rats was to that of rats not the action of insulin in GP did not the of insulin on GP, but the of the of insulin on GP is as a of inhibition GP by in the of but by was When was to alter the action of insulin on GP whereas alone did not alter hepatic insulin action the of the central administration of on GP is because the inhibition of central melanocortin receptors is to the effects of on hepatic insulin action. the of a in the rate of GP as the was by the administration of whereas the administration of an of the melanocortin did not GP. the the effects of on GP, we the in vivo through glucose-6-phosphatase and the of glycogenolysis and gluconeogenesis to glucose the in the of either gluconeogenesis or glycogenolysis to in GP by was by a in the through an that was also by the of marked effects of on GP and glucose-6-phosphatase were by a in the rate of gluconeogenesis the whereas the of glycogenolysis were not of on gluconeogenesis was by the of a melanocortin we examined whether changes in the expression of the gluconeogenic enzymes Glc-6-Pase and PEPCK changes in hepatic glucose fluxes. activation of melanocortin receptors to hepatic expression of Glc-6-Pase and PEPCK changes were also by the central administration of and we a and of the central melanocortin pathway on gluconeogenesis and on hepatic Glc-6-Pase and PEPCK we also a of the melanocortin that the effects of but on glucose fluxes or an to the of central melanocortin receptors to the of of Systemic Leptin on examined whether and central of melanocortin receptors the effects of leptin on hepatic glucose fluxes. of rats a infusion of either or leptin and in insulin and and and were in the and the the rate of glucose infusion to the glucose was not by leptin but was by the infusion of of glucose were in rats or leptin or not the of leptin and the action of insulin in GP the of insulin on GP is as the of inhibition GP by in the of leptin alone did not alter hepatic insulin action was leptin resulted in suppression of GP the central administration of an of the melanocortin receptors a melanocortin-independent of leptin on hepatic insulin action. the the effects of leptin on GP, we the in vivo through glucose-6-phosphatase and the of glycogenolysis and and gluconeogenesis to glucose the of leptin did not the rate of GP as the the administration of leptin and markedly decreased GP decrease in GP by the of leptin and was by a marked decrease in the through L. Massillon D. Barzilai N. Vuguin P. Chen W. Hawkins M. Wu J. Wang J. J. Biol. Chem. 1997; 272: 27758-27763Abstract Full Text Full Text PDF PubMed Scopus (274) Google the infusion of recombinant leptin markedly gluconeogenesis by leptin also markedly decreased the rate of glycogenolysis in to and was not by the central of melanocortin receptors the of leptin on gluconeogenesis was by the infusion of a melanocortin the marked effects of leptin and on GP and glucose-6-phosphatase were by a marked decrease in the rate of glycogenolysis the and by a marked decrease in the rate of gluconeogenesis the we examined whether changes in the expression of Glc-6-Pase and PEPCK changes in hepatic glucose fluxes. because central activation of melanocortin receptors as well as leptin infusion to hepatic expression of Glc-6-Pase and we that the activation of central melanocortin receptors of Indeed, the central administration of also hepatic effects of leptin and the of the leptin infusion on gluconeogenesis and on hepatic Glc-6-Pase and PEPCK activation of central melanocortin the of leptin on hepatic glycogenolysis is of activation of the central melanocortin effects of leptin on hepatic insulin signaling and glycogenolysis in or in D. M. H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (216) Google Scholar, J. Wang J. M. J.K. 2004; PubMed Scopus Google Scholar, W. N. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). is important to whether the melanocortin-independent effects of leptin on hepatic glucose fluxes also in to the central administration of of Leptin on examined whether and central of melanocortin receptors the effects of the central administration of leptin on hepatic glucose fluxes. of rats either an infusion of or leptin or leptin and in insulin and and were in the and the the rate of glucose infusion to the glucose was not by leptin but was by the infusion of of glucose were in rats or leptin or not the of leptin and the action of insulin in GP the of insulin on GP is as a of inhibition GP by in the of leptin alone did not alter hepatic insulin action was leptin resulted in suppression of GP the central administration of an of the melanocortin receptors a melanocortin-independent of central leptin on hepatic insulin action. the the effects of leptin on GP, we the in vivo through glucose-6-phosphatase and the of glycogenolysis and gluconeogenesis to glucose the of leptin did not the rate of GP as the the administration of leptin and markedly decreased GP decrease in GP by the of leptin and was by a marked decrease in the through L. Karkanias G.B. Morales J.C. Hawkins M. Barzilai N. Wang J. Rossetti L. J. Biol. Chem. 1998; 273: 31160-31167Abstract Full Text Full Text PDF PubMed Scopus (188) Google the infusion of recombinant leptin markedly gluconeogenesis by leptin also markedly decreased the rate of glycogenolysis in to and was not by the central of melanocortin receptors the of leptin on gluconeogenesis was by the infusion of a melanocortin the marked effects of central leptin and on GP and glucose-6-phosphatase were by a marked decrease in the rate of glycogenolysis the and by a marked decrease in the rate of gluconeogenesis the we examined whether changes in the expression of Glc-6-Pase and PEPCK changes in hepatic glucose fluxes. Because central activation of melanocortin receptors as well as or leptin infusion to hepatic expression of Glc-6-Pase and we that of leptin is via activation of central melanocortin Indeed, the central administration of also hepatic effects of leptin and the of the central administration of leptin on gluconeogenesis and on hepatic Glc-6-Pase and PEPCK activation of central melanocortin the of leptin on hepatic glycogenolysis is of activation of the central melanocortin is increasing central nervous system energy and glucose homeostasis (4Shimomura I. Hammer R.E. Ikemoto S. Brown M.S. Goldstein J.L. Nature. 1999; 401: 73-76Crossref PubMed Scopus (873) Google Scholar, 5Rossetti L. Massillon D. Barzilai N. Vuguin P. Chen W. Hawkins M. Wu J. Wang J. J. Biol. Chem. 1997; 272: 27758-27763Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar, 6Liu L. Karkanias G.B. Morales J.C. Hawkins M. Barzilai N. Wang J. Rossetti L. J. Biol. Chem. 1998; 273: 31160-31167Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar, 7Shimabukuro M. Koyama K. Chen G. Wang M.Y. Trieu F. Lee Y. Newgard C.B. Unger R.H. Proc. Natl. Acad. Sci. U. S. A. 1997; 94: 4637-4641Crossref PubMed Scopus (623) Google Scholar, 8Bai Y. Zhang S. Kim K.S. Lee J.K. Kim K.H. J. Biol. Chem. 1996; 271: 13939-13942Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar, 9Lord G.M. Matarese G. Howard J.K. Baker R.J. Bloom S.R. Lechler R.I. Nature. 1998; 394: 897-901Crossref PubMed Scopus (1865) Google Scholar, N. Wang J. Massilon D. Vuguin P. Hawkins M. Rossetti L. J. Clin. Invest. 1997; 100: 3105-3110Crossref PubMed Scopus (297) Google Scholar, 11Chinookoswong N. Wang J.L. Shi Z.Q. Diabetes. 1999; 48: 1487-1492Crossref PubMed Scopus (164) Google Scholar, 12Yaspelkis B.B. II I Davis J.R. Saberi M. Smith T.L. Jazayeri R. Singh M. Fernandez V. Trevino B. Chinookoswong N. Wang J. Shi Z.Q. Levin N. Am. J. Physiol. 2001; 280: E130-E142PubMed Google Scholar, 13Hidaka S. Yoshimatsu H. Kondou S. Tsuruta Y. Oka K. Noguchi H. Okamoto K. Sakino H. Teshima Y. Okeda T. Sakata T. FASEB J. 2002; 16: 509-518Crossref PubMed Scopus (90) Google Scholar, 14Petersen K.F. Oral E.A. Dufour S. Befroy D. Ariyan C. Yu C. Cline G.W. DePaoli A.M. Taylor S.I. Gorden P. Shulman G.I. J. Clin. Invest. 2002; 109: 1345-1350Crossref PubMed Scopus (640) Google Scholar, 15Obici S. Feng Z. Tan J. Liu L. Karkanias G. Rossetti L. J. Clin. Invest. 2001; 108: 1079-1085Crossref PubMed Scopus (324) Google Scholar, M.W. Baskin D.G. J.L. D. G. Jr., D. S.C. R.J. Diabetes. 1996; PubMed Google Scholar, Z.Q. A. L. Wang J. A.M. 1998; Full Text PDF PubMed Scopus Google Scholar). leptin is a of peripheral energy acts mainly on hypothalamic receptors to regulate and energy (1Friedman J.M. Halaas J.L. Nature. 1998; 395: 763-770Crossref PubMed Scopus (4580) Google Scholar, M.W. S.C. Jr., D. R.J. Baskin D.G. Nature. PubMed Scopus Google Scholar). Y. R. M. M. L. J.M. Nature. PubMed Scopus Google leptin was also to regulate glucose insulin and lipid metabolism of effects L. Massillon D. Barzilai N. Vuguin P. Chen W. Hawkins M. Wu J. Wang J. J. Biol. Chem. 1997; 272: 27758-27763Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar, 6Liu L. Karkanias G.B. Morales J.C. Hawkins M. Barzilai N. Wang J. Rossetti L. J. Biol. Chem. 1998; 273: 31160-31167Abstract Full Text Full Text PDF PubMed Scopus (188) Google Scholar, N. Wang J. Massilon D. Vuguin P. Hawkins M. Rossetti L. J. Clin. Invest. 1997; 100: 3105-3110Crossref PubMed Scopus (297) Google Scholar, M.W. Baskin D.G. J.L. D. G. Jr., D. S.C. R.J. Diabetes. 1996; PubMed Google Scholar, Jr., R.A. Diabetes. 1997; PubMed Google Scholar, R.A. Am. J. Physiol. 1999; Google Scholar). in the of the by leptin leptin central melanocortin receptors partly via of the and via decreased of a the of the hypothalamus J.L. M. S. T.L. Nature. 2001; PubMed Scopus Google Scholar). activation of the central melanocortin pathway to a in action on food energy nervous insulin and body distribution N. Coppari R. McMinn J. Liu S.M. Lee C.E. Tang V. Kenny C.D. McGovern R.A. Chua Jr., S.C. Elmquist J.K. Lowell B.B. Neuron. 2004; 42: 983-991Abstract Full Text Full Text PDF PubMed Scopus (740) Google Scholar, N. Wang J. Massilon D. Vuguin P. Hawkins M. Rossetti L. J. Clin. Invest. 1997; 100: 3105-3110Crossref PubMed Scopus (297) Google Scholar, 16Barzilai N. She L. Liu L. Wang J. Hu M. Vuguin P. Rossetti L. Am. J. Physiol. 1999; 277: E291-E298PubMed Google Scholar, 2004; PubMed Scopus Google Scholar, A. 1999; PubMed Google Scholar, K. J. PubMed Google Scholar, R. G. J. Karkanias G. Barzilai N. FASEB J. PubMed Scopus Google Scholar). is also the effects of leptin on energy balance and intermediate metabolism that of the activation of central melanocortin receptors M. Wang Y. Schwartz M.W. Jr., Nature. PubMed Scopus Google Scholar). we melanocortin-dependent and melanocortin-independent effects of leptin on hepatic glucose fluxes and leptin stimulates gluconeogenesis and the hepatic expression of PEPCK and Glc-6-Pase via central activation of melanocortin On the other hand, the or central administration of leptin also hepatic glycogenolysis via a central melanocortin-independent acute and central activation of melanocortin receptors the expression of gluconeogenic enzymes within the markedly the rate of gluconeogenesis, and the of insulin on GP. of the central modulation of the melanocortin pathway in the insulin effects of prolonged of the central melanocortin activation of central pathway to decreased adiposity and insulin action (15Obici S. Feng Z. Tan J. Liu L. Karkanias G. Rossetti L. J. Clin. Invest. 2001; 108: 1079-1085Crossref PubMed Scopus (324) Google Scholar). in the signaling via the central melanocortin receptors is or glucose and D. V. W. R.A. Smith Burn P. Lee F. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). acute and effects of central melanocortin modulation to the effects of pathway on body and lipid and and nervous system the activation of the melanocortin pathway in the central nervous system is to to peripheral in the of changes in adiposity and lipid (15Obici S. Feng Z. Tan J. Liu L. Karkanias G. Rossetti L. J. Clin. Invest. 2001; 108: 1079-1085Crossref PubMed Scopus (324) Google Scholar, D. V. W. R.A. Smith Burn P. Lee F. 1997; Full Text Full Text PDF PubMed Scopus Google Scholar). the an in leads to expression of Glc-6-Pase and PEPCK and to in effects of leptin on hepatic glucose fluxes to of infusion of leptin insulin the hepatic expression of PEPCK and Glc-6-Pase and the rate of gluconeogenesis, but also markedly the rate of glycogenolysis that GP was not changes by a in leptin in the of of the L. Massillon D. Barzilai N. Vuguin P. Chen W. Hawkins M. Wu J. Wang J. J. Biol. Chem. 1997; 272: 27758-27763Abstract Full Text Full Text PDF PubMed Scopus (274) Google Scholar). When the of leptin on central melanocortin receptors was prevented, in leptin to alter gluconeogenesis and increasing the leptin markedly the rate of glycogenolysis and the inhibition of GP by It that effects of leptin on hepatic glucose fluxes via effects on the as well as via of leptin also to insulin lipid and glycogenolysis in some in D. M. H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus (216) Google Scholar, J. Wang J. M. J.K. 2004; PubMed Scopus Google Scholar) or W. N. J. Biol. Chem. 2004; Full Text Full Text PDF PubMed Scopus Google Scholar). the effects of a in leptin on the hepatic expression of gluconeogenic enzymes as well as on gluconeogenesis because were by the central of melanocortin whether the melanocortin-independent effects of leptin on glycogenolysis and GP to leptin or whether also we examined the effects of central leptin administration or activation of central melanocortin leptin markedly GP via decreased glycogenolysis, the activation of central melanocortin receptors was leptin hepatic glycogenolysis and GP via a central is the that of leptin expression the and by the body in P. C. J.M. S.C. P. P. J.M. J. Clin. Invest. 2001; 108: PubMed Scopus Google Scholar). the central nervous system and the melanocortin-independent effects of leptin on glycogenolysis is to that the activation of an signaling pathway within the hypothalamus plays a Leptin and insulin both the activity of in the and signaling pathway is in their effects Jr., Schwartz M.W. Nature. 2001; PubMed Scopus Google Scholar, C.D. R. Baskin D.G. Jr., R.J. Schwartz M.W. Diabetes. PubMed Scopus Google Scholar). central activation of insulin signaling markedly GP, and the of a in insulin on GP the central activation of S. Zhang B.B. Karkanias G. Rossetti L. 2002; PubMed Scopus Google Scholar). we the effects of leptin via a melanocortin-independent signaling pathway that the of the central administration of insulin on GP. the that activation of by leptin in the hypothalamus on GP and glycogenolysis. It recognized that the of insulin to glucose production by the insulin is a of in that leptin hepatic insulin action via melanocortin-dependent as well as via melanocortin-independent effects leptin stimulates hepatic gluconeogenesis and expression via central activation of melanocortin but also markedly hepatic glycogenolysis via a central melanocortin-independent signaling via either of central the of leptin on the to changes in hepatic insulin action and glucose important to whether of leptin on the melanocortin-dependent and melanocortin-independent effects of leptin on glucose