The incretin receptor GLP1R for instance, which is the current prime target for obesity treatment, modulates food intake and insulin secretion, but energy expenditure itself remains unaltered.2 Subcutaneous versus intracerebroventricular agonist administration reveals that NK2R activation acts via both the periphery and the central nervous system to simultaneously suppress appetite, increase energy expenditure, and improve insulin sensitivity, thereby suggesting two different underpinning mechanisms. The gene discussed is TACR2; the disease is obesity due to melanocortin 4 receptor deficiency.