Leptin and insulin induce mutual resistance for nitric oxide synthase III activation in adipocytes.
Obesity-induced hyperleptinemia is frequently associated with insulin resistance suggesting a crosstalk between leptin and insulin signaling pathways. Our aim was to determine whether insulin and leptin together interfere on NOS activation in adipocytes. We examined insulin and leptin-induced nitric oxide synthase (NOS) activity, protein amount and NOS III phosphorylation at Ser(1179) in isolated epididymal adipocytes from rat, in the presence or not of inhibitors of kinases implicated in insulin or leptin signaling pathways. Insulin or leptin induced NOS III phosphorylation at Ser(1179) leading to increased NO production in rat adipocytes, in agreement with our previous observations. When insulin and leptin at a concentration found in obese rats (10 ng/ml) were combined, NOS activity was not increased, suggesting a negative crosstalk between insulin and leptin signaling mechanisms. Chemical inhibitors of kinases implicated in signaling pathways of insulin, such as PI-3 kinase, or of leptin, such as JAK-2, did not prevent this negative interaction. When leptin signaling was blocked by PKA inhibitors, insulin-induced NOS activity and NOS III phosphorylation at Ser(1179) was observed. In the presence of leptin and insulin, (i) IRS-1 was phosphorylated on Ser(307) and this effect was prevented by PKA inhibitors, (ii) JAK-2 was dephosphorylated, an effect prevented by SHP-1 inhibitor. A mutual resistance occurs with leptin and insulin. Leptin phosphorylates IRS-1 to induce insulin resistance while insulin dephosphorylates JAK-2 to favor leptin resistance. This interference between insulin and leptin signaling could play a crucial role in insulin- and leptin-resistance correlated with obesity.
Mehebik-Mojaat
Nadia
N
Institut National de la Santé et de la Recherche Médicale UMR-S 747, Université Paris Descartes, Pharmacologie Toxicologie et Signalisation Cellulaire, 45 rue des Saints-Pères, 75006 Paris, France.
Ribière
Catherine
C
Niang
Fatoumata
F
Forest
Claude
C
Jaubert
Anne-Marie
AM
D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D004789:Enzyme Activation; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D020738:Leptin / Q000378:metabolism*; D008297:Male; D008954:Models, Biological; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley
D007328:Insulin; D020738:Leptin; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D019869:Phosphatidylinositol 3-Kinases