These data demonstrate that intact male animals fed a HFD exhibit greater retrograde inhibition of glutamatergic neurotransmission at VMN SF-1/ARC POMC synapses, whereas their female counterparts do not, which further substantiates the notion that diet-induced obesity/insulin resistance is associated with a sexually differentiated enhancement of EC tone within the hypothalamic energy balance circuitry. Here, POMC is linked to obesity disorder.