Chronic central leptin infusion modifies the response to acute central insulin injection by reducing the interaction of the insulin receptor with IRS2 and increasing its association with SOCS3.

Leptin and insulin have overlapping intracellular signaling mechanisms and exert anorexigenic actions in the hypothalamus. We aimed to determine how chronic exposure to increased leptin affects the hypothalamic response to a rise in insulin. We analyzed the activation and interactions of components of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway in the hypothalamus of rats treated icv for 14 days with leptin followed by a central injection of insulin and killed 15 min later. Insulin increased glycemia and chronic leptin reduced this insulin induced rise in glucose. Leptin decreased the association between the insulin receptor beta chain (IRβ) and insulin receptor substrate 2 (IRS2), augmented the association between Janus kinase 2 and IRS2, increased levels of the catalytic subunit of PI3K and pAkt-Ser473 and decreased forkhead box O number 1 levels. Insulin reduced the association between suppressor of the cytokine signaling 3 and IRβ, increased IRβ-IRS2 association and pAkt-Thr308 levels, with chronic leptin exposure blunting these effects. In conclusion, chronic exposure to leptin decreases the central response to insulin by increasing suppressor of the cytokine signaling 3 association to IR, which inhibits insulin signaling at the level of interaction of its receptor with IRS2 and activates PI3K by promoting Janus kinase 2-IRS2 association. Thus, these results suggest that this mechanism could be a target for the treatment of insulin resistance.