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Intracellular Leptin-Signaling Pathways in Hypothalamic Neurons: The Emerging Role of Phosphatidylinositol-3 Kinase-Phosphodiesterase-3B-cAMP Pathway

Leptin is secreted primarily by fat cells and acts centrally, particularly in the hypothalamus, to reduce food intake and body weight. Besides the classical JAK2 (Janus kinase-2)-STAT3 (signal transducer and activator of transcription-3) pathway, several non-STAT3 pathways play an important role in mediating leptin signaling in the hypothalamus. We have demonstrated that leptin action in the hypothalamus is mediated by an insulin-like signaling pathway involving stimulation of PI3K (phosphatidylinositol-3 kinase) and PDE3B (phosphodiesterase-3B), and reduction in cAMP levels, and that a PI3K-PDE3B-cAMP pathway interacting with the JAK2-STAT3 pathway constitutes a critical component of leptin signaling in the hypothalamus. It appears that defective regulation of multiple signaling pathways in the hypothalamus causes central leptin resistance, a major cause of obesity. In this regard, we have shown that leptin resistance in hypothalamic neurons following chronic central infusion of this hormone is associated with a defect in the PI3K-PDE3B-cAMP, and not due to compromised signaling in the JAK2-STAT3 pathway. Similarly, the PI3K, but not the STAT3, pathway is impaired in the hypothalamus during the development of diet-induced obesity. Additionally, our recent work suggests that suppressor of cytokine signaling-3 negatively regulates the PI3K pathway of leptin signaling in the hypothalamus, a mechanism expected to play a significant role in diet-induced obesity. Together, the PI3K-PDE3B-cAMP pathway appears to emerge as a major mechanism of leptin signaling in the hypothalamus in regulating energy balance.