Therefore, the primary effect of intervening in hypothalamic insulin signaling on glucose metabolism can be demonstrated only by: (1) The lack of a significant effect on body weight; (2) an acute-phase intervention such as 1–3 days of a high fat diet (HFD), during which it is still too early for obesity to occur; or (3) food restriction in the orexigenic or to-be-obese group to match body weights between groups (pair-feeding). Here, INS is linked to obesity due to melanocortin 4 receptor deficiency.