Since hormones like E2 act through PI3K/Akt to diminish EC tone at VMN SF-1/ARC POMC synapses (Mela et al., 2016), it stands to reason that decreased ARC PI3K/Akt signaling observed with diet-induced obesity/insulin resistance in males would do just the opposite (Figure 13). This evidence concerns the gene SF1 and obesity due to melanocortin 4 receptor deficiency.