Mch and mchr1 knock-out mice are hyperactive and resistant to diet-induced obesity [13–15]; discoveries that initiated years of research into the targeted disruption of MCH signalling for clinical use in humans, however the mechanisms responsible for MCH-mediated actions are unclear and as an additional hurdle, most available MCHR1 antagonists that made it to clinical trials had off-target effects at the hERG channel, until only very recently [16,17]. Here, PMCH is linked to obesity due to melanocortin 4 receptor deficiency.