Obesity and Gαs Variants

This editorial discusses the discovery of GNAS gene variants encoding the stimulatory G protein alpha subunit (Gαs) and their association with severe obesity due to impaired melanocortin 4 receptor (MC4R) signaling. The GNAS locus, known for its role in pseudohypoparathyroidism (PHP1A, PHP1B), produces Gαs, which mediates cyclic AMP signaling for multiple G protein-coupled receptors (GPCRs). Mendes de Oliveira et al. identified 19 heterozygous GNAS mutations in patients with early-onset obesity, revealing a spectrum of PHP1A-like phenotypes without classic hormone resistance. The mutations, predominantly maternal, caused hyperphagia and obesity but minimal skeletal abnormalities. The findings suggest GNAS variants may underlie isolated obesity and highlight potential therapeutic avenues, such as MC4R agonists or cyclic AMP modulators, to address receptor-specific signaling defects.

This editorial discusses the discovery of GNAS gene variants encoding the stimulatory G protein alpha subunit (Gαs) and their association with severe obesity due to impaired melanocortin 4 receptor (MC4R) signaling. The GNAS locus, known for its role in pseudohypoparathyroidism (PHP1A, PHP1B), produces Gαs, which mediates cyclic AMP signaling for multiple G protein-coupled receptors (GPCRs). Mendes de Oliveira et al. identified 19 heterozygous GNAS mutations in patients with early-onset obesity, revealing a spectrum of PHP1A-like phenotypes without classic hormone resistance. The mutations, predominantly maternal, caused hyperphagia and obesity but minimal skeletal abnormalities. The findings suggest GNAS variants may underlie isolated obesity and highlight potential therapeutic avenues, such as MC4R agonists or cyclic AMP modulators, to address receptor-specific signaling defects.