ARRB2 and obesity due to melanocortin 4 receptor deficiency: Specifically, carriers of GIPR variants that are pharmacologically classified as loss-of-function variants with reduced cell surface expression, cAMP production, beta arrestin 2 recruitment, internalization, and endosomal signaling have consistently been associated with lower adiposity-related traits, including BMI (103) and nominally lower prevalence of obesity (39, 97–99).