This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Anderwald, C. Articles by Roden, M. Search for Related Content PubMed PubMed Citation Articles by Anderwald, C. Articles by Roden, M.

Short-Term Leptin-Dependent Inhibition of Hepatic Gluconeogenesis Is Mediated by Insulin Receptor Substrate-2

Division of Endocrinology and Metabolism (C.A., G.K., C.F., W.W., M.R.), Department of Internal Medicine III, University of Vienna, Austria A-1090; and Division of Metabolic Diseases (G.M.), Aventis Pharma Frankfurt/Main D-65925, Germany

Address all correspondence and requests for reprints to: Michael Roden, M.D., Division of Endocrinology and Metabolism, Department of Internal Medicine III, University of Vienna, Währinger Gürtel 18–20, A-1090 Vienna, Austria. E-mail: michael.roden{at}akh-wien.ac.at.

Leptin has both insulin-like and insulin-antagonistic effects on glucose metabolism. To test whether leptin interferes directly with insulin signaling, we perfused isolated rat livers with leptin (0.1, 0.5, 5, and 25 nmol/liter), leptin + insulin (5 nmol/liter + 10 nmol/liter), insulin (10 nmol/liter), or vehicle (control). Leptin reduced L-lactate-(10 mmol/liter)-stimulated glucose production by 39–66% (P < 0.006 vs. control) and phosphoenolpyruvate carboxykinase (PEPCK) activity by 22–52% (P < 0.001). Physiological leptin concentrations (0.1–5 nmol/liter) stimulated the tyrosine phosphorylation (pY) of insulin receptor substrate-2 (IRS-2) (280–954%; P < 0.05) and its associated phosphatidylinositol-3 kinase activity (122–621%; P < 0.003). Leptin (0.5–25 nmol/liter) inhibited IRS-1 pY and its associated phosphatidylinositol-3 kinase activity (20–89%; P < 0.03) but stimulated janus kinase-2 pY (272–342%; P < 0.001). Leptin also down-regulated its short receptor isoform in a time- and concentration-dependent manner (28–54%; P < 0.05). Exposure to leptin + insulin additively reduced glucose production and PEPCK activity (50%; P < 0.001 vs. control) and doubled IRS-2 pY (P < 0.01 vs. insulin). However, leptin + insulin decreased IRS-1 pY by 57% (P < 0.01 vs. insulin). Insulin alone (P < 0.01), but not leptin, increased autophosphorylation of nonreceptor tyrosine kinases (pp59^Lyn + pp125^Fak).

In conclusion, leptin both alone and in combination with insulin reduces hepatic glucose production by decreasing the synthesis of the key enzyme of gluconeogenesis, PEPCK, which results mainly from the stimulation of the IRS-2 pathway.

This article has been cited by other articles:

				L. Jiang, Z. Li, and L. Rui Leptin Stimulates Both JAK2-dependent and JAK2-independent Signaling Pathways J. Biol. Chem., October 17, 2008; 283(42): 28066 - 28073. [Abstract] [Full Text] [PDF]

				A. J. Forhead, C. A. Lamb, K. L. Franko, D. M. O'Connor, F. B. P. Wooding, R. L. Cripps, S. Ozanne, D. Blache, Q. W. Shen, M. Du, et al. Role of leptin in the regulation of growth and carbohydrate metabolism in the ovine fetus during late gestation J. Physiol., May 1, 2008; 586(9): 2393 - 2403. [Abstract] [Full Text] [PDF]

				M. Promintzer, M. Krebs, J. Todoric, A. Luger, M. G. Bischof, P. Nowotny, O. Wagner, H. Esterbauer, and C. Anderwald Insulin Resistance Is Unrelated to Circulating Retinol Binding Protein and Protein C Inhibitor J. Clin. Endocrinol. Metab., November 1, 2007; 92(11): 4306 - 4312. [Abstract] [Full Text] [PDF]

				N T Lam, S D Covey, J T Lewis, S Oosman, T Webber, E C Hsu, A T Cheung, and T J Kieffer Leptin resistance following over-expression of protein tyrosine phosphatase 1B in liver J. Mol. Endocrinol., February 1, 2006; 36(1): 163 - 174. [Abstract] [Full Text] [PDF]

				P. M. Thule, A. G. Campbell, D. J. Kleinhenz, D. E. Olson, J. J. Boutwell, R. L. Sutliff, and C. M. Hart Hepatic insulin gene therapy prevents deterioration of vascular function and improves adipocytokine profile in STZ-diabetic rats Am J Physiol Endocrinol Metab, January 1, 2006; 290(1): E114 - E122. [Abstract] [Full Text] [PDF]

				M. W. Schwartz and K. D. Niswender Adiposity Signaling and Biological Defense Against Weight Gain: Absence of Protection or Central Hormone Resistance? J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 5889 - 5897. [Abstract] [Full Text] [PDF]

				C. Duan, M. Li, and L. Rui SH2-B Promotes Insulin Receptor Substrate 1 (IRS1)- and IRS2-mediated Activation of the Phosphatidylinositol 3-Kinase Pathway in Response to Leptin J. Biol. Chem., October 15, 2004; 279(42): 43684 - 43691. [Abstract] [Full Text] [PDF]

				U. Hanusch-Enserer, E. Cauza, G. Brabant, A. Dunky, H. Rosen, G. Pacini, H. Tuchler, R. Prager, and M. Roden Plasma Ghrelin in Obesity before and after Weight Loss after Laparoscopical Adjustable Gastric Banding J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3352 - 3358. [Abstract] [Full Text] [PDF]

				R. Suzuki, K. Tobe, M. Aoyama, A. Inoue, K. Sakamoto, T. Yamauchi, J. Kamon, N. Kubota, Y. Terauchi, H. Yoshimatsu, et al. Both Insulin Signaling Defects in the Liver and Obesity Contribute to Insulin Resistance and Cause Diabetes in Irs2-/- Mice J. Biol. Chem., June 11, 2004; 279(24): 25039 - 25049. [Abstract] [Full Text] [PDF]

				N. T. Lam, J. T. Lewis, A. T. Cheung, C. T. Luk, J. Tse, J. Wang, M. Bryer-Ash, J. K. Kolls, and T. J. Kieffer Leptin Increases Hepatic Insulin Sensitivity and Protein Tyrosine Phosphatase 1B Expression Mol. Endocrinol., June 1, 2004; 18(6): 1333 - 1345. [Abstract] [Full Text] [PDF]

				W. Huang, N. Dedousis, B. A. Bhatt, and R. M. O'Doherty Impaired Activation of Phosphatidylinositol 3-Kinase by Leptin Is a Novel Mechanism of Hepatic Leptin Resistance in Diet-induced Obesity J. Biol. Chem., May 21, 2004; 279(21): 21695 - 21700. [Abstract] [Full Text] [PDF]

				C. Anderwald, G. Brabant, E. Bernroider, R. Horn, A. Brehm, W. Waldhausl, and M. Roden Insulin-Dependent Modulation of Plasma Ghrelin and Leptin Concentrations Is Less Pronounced in Type 2 Diabetic Patients Diabetes, July 1, 2003; 52(7): 1792 - 1798. [Abstract] [Full Text] [PDF]

				K. D. Niswender, B. Gallis, J. E. Blevins, M. A. Corson, M. W. Schwartz, and D. G. Baskin Immunocytochemical Detection of Phosphatidylinositol 3-kinase Activation by Insulin and Leptin J. Histochem. Cytochem., March 1, 2003; 51(3): 275 - 283. [Abstract] [Full Text] [PDF]