We have provided definitive evidence that gain-of-function BRSK2 in β cells directly initiates β-cell hypersecretion, insulin resistance, and GSIS disability in mice, while loss-of-function BRSK2 in adulthood restrains diet-induced obesity and maintains GSIS function to prevent diabetes insult. This evidence concerns the gene BRSK2 and obesity due to melanocortin 4 receptor deficiency.