Finally, to investigate whether the FNDC4–GPR116 axis responded to preventive or therapeutic approaches against T2D, we examined the regulation of the ligand–receptor system in human cohorts of weight loss interventions with either bariatric surgery (BS) or diet/exercise and in mouse models of weight gain prevention using intermittent fasting or caloric restriction (CR). Here, ADGRF5 is linked to type 2 diabetes mellitus.