INS and overnutrition: Specifically, overnutrition activates hypothalamic IKKβ/NF-κB, a well-known mediator of metabolic inflammation, which elicits ER stress (which also promotes IKKβ/NF-κB) and initiates UPR signaling pathways in the hypothalamus, which in turn directs to inhibition of leptin receptor signaling pathway (STAT3, SOCS3, and PTP1B) and insulin and leptin resistance [23]–[25].