RGD Reference Report - Short-term leptin-dependent inhibition of hepatic gluconeogenesis is mediated by insulin receptor substrate-2. - Rat Genome Database

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Short-term leptin-dependent inhibition of hepatic gluconeogenesis is mediated by insulin receptor substrate-2.

Authors: Anderwald, C  Muller, G  Koca, G  Furnsinn, C  Waldhausl, W  Roden, M 
Citation: Anderwald C, etal., Mol Endocrinol 2002 Jul;16(7):1612-28.
RGD ID: 1299203
Pubmed: PMID:12089355   (View Abstract at PubMed)
DOI: DOI:10.1210/mend.16.7.0867   (Journal Full-text)

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.

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process
TermQualifierEvidenceWithReferenceNotesSourceOriginal Reference(s)
response to insulin  IEP 1299203RGD: 731056RGD 

Objects Annotated

Genes (Rattus norvegicus)
Lyn  (LYN proto-oncogene, Src family tyrosine kinase)

Objects referenced in this article
Gene Irs2 insulin receptor substrate 2 Rattus norvegicus
Gene Lep leptin Rattus norvegicus

Additional Information