Insulin signals via IRS-PI3K to activate TRPC 5 channels in POMC neurons, which generates a robust inward cationic current to depolarize POMC neurons and increase their excitability. Similarly, leptin binding to its receptor (LRb) triggers the recruitment of the tyrosine kinase Janus kinase (JAK) 2, leading to the activation of the JAK/signal transducer and activator of transcription (STAT) signaling pathway and simultaneously activation of PI3K, which also activates TRPC 5 channels. PI3K (p85/p110) will also accelerate the rapid insertion of TPRC 5 channels into the plasma membrane. PDK1, 3-phosphoinositide–dependent protein kinase-1. [Modified from Fig. 8, Qiu et al., 2018a. Endocrinology 159, 647-664.]