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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 &lt; 0.006 vs. control) and phosphoenolpyruvate carboxykinase (PEPCK) activity by 22-52% (P &lt; 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 &lt; 0.05) and its associated phosphatidylinositol-3 kinase activity (122-621%; P &lt; 0.003). Leptin (0.5-25 nmol/liter) inhibited IRS-1 pY and its associated phosphatidylinositol-3 kinase activity (20-89%; P &lt; 0.03) but stimulated janus kinase-2 pY (272-342%; P &lt; 0.001). Leptin also down-regulated its short receptor isoform in a time- and concentration-dependent manner (28-54%; P &lt; 0.05). Exposure to leptin + insulin additively reduced glucose production and PEPCK activity (approximately 50%; P &lt; 0.001 vs. control) and doubled IRS-2 pY (P &lt; 0.01 vs. insulin). However, leptin + insulin decreased IRS-1 pY by 57% (P &lt; 0.01 vs. insulin). Insulin alone (P &lt; 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.

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