Short-term leptin-dependent inhibition of hepatic gluconeogenesis is mediated by insulin receptor substrate-2.
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 (approximately 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.
Anderwald
Christian
C
Division of Endocrinology and Metabolism, Department of Internal Medicine III, University of Vienna, Austria A-1090.
Müller
Günter
G
Koca
Georg
G
Fürnsinn
Clemens
C
Waldhäusl
Werner
W
Roden
Michael
M
D000818:Animals; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; D005943:Gluconeogenesis / Q000502:physiology*; D006003:Glycogen / Q000378:metabolism; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D066298:In Vitro Techniques; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2; D019344:Lactic Acid / Q000378:metabolism; D020738:Leptin / Q000378:metabolism* / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000502:physiology*; D008297:Male; D010477:Perfusion; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D051381:Rats; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D054411:Receptors, Leptin; D019061:src-Family Kinases / Q000378:metabolism
D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526296:Irs1 protein, rat; C526299:Irs2 protein, rat; D020738:Leptin; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D019344:Lactic Acid; D006003:Glycogen; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D051417:Focal Adhesion Kinase 1; D051416:Focal Adhesion Protein-Tyrosine Kinases; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; C496052:Ptk2 protein, rat; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases; D038362:Glycogen Synthase Kinase 3; D019764:Phosphoenolpyruvate Carboxykinase (ATP)