Gsα couples multiple receptors to intracellular cAMP generation. Germline inactivating Gsα mutations lead to obesity in humans and mice. Mice with brain-specific Gsα deficiency also develop obesity with reduced energy expenditure and locomotor activity, and impaired adaptive thermogenesis, but the underlying mechanisms remain unclear. Chen et al. created mice with complete Gsα deficiency in the dorsomedial hypothalamus. These mice develop severe early-onset obesity associated with hyperphagia, along with decreases in energy expenditure. This is associated with impaired leptin signaling.