Mendes de Oliveira and colleagues now report in the Journal that variants in GNAS exons that encode the stimulatory G-protein alpha subunit (Gαs) have a strong genetic association with severe obesity, owing to reduced signaling by the melanocortin 4 receptor (MC4R) and possible signaling abnormalities at other G protein–coupled receptors (GPCRs).1 Given the multitude of biologic functions mediated by Gαs, which is best known among the various GNAS-derived transcripts and proteins, and the well-established clinical and laboratory abnormalities encountered in pseudohypoparathyroidism type 1a and 1b (PHP1A and PHP1B, respectively), these exciting findings are not entirely unexpected. Gαs serves a diverse . . .