Disruption of the RIIβ subunit of PKA reverses the obesity syndrome of agouti lethal yellow mice

Agouti lethal yellow (A(y)) mice express agouti ectopically because of a genetic rearrangement at the agouti locus. The agouti peptide is a potent antagonist of the melanocortin 4 receptor (MC4R) expressed in neurons, and this leads to hyperphagia, hypoactivity, and increased fat mass. The MC4R signals through Gs and is thought to stimulate the production of cAMP and activation of downstream cAMP effector molecules such as PKA. Disruption of the RII beta regulatory subunit gene of PKA results in release of the active catalytic subunit and an increase in basal PKA activity in cells where UP is highly expressed. Because RII beta is expressed in neurons including those in the hypothalamic nuclei where MC4R is prominent we tested the possibility that the RII beta knockout might rescue the body weight phenotypes of the A(y) mice. Disruption of the RII beta PKA regulatory subunit gene in mice leads to a 50% reduction in white adipose tissue and resistance to diet-induced obesity and hyperglycemia. The RII beta mutation rescued the elevated body weight, hyperphagia, and obesity of A(y) mice. Partial rescue of the A(y) phenotypes was even observed on an RII beta heterozygote background. These results suggest that the RII beta gene mutation alters adiposity and locomotor activity by modifying PKA signaling pathways downstream of the agouti antagonism of MC4R in the hypothalamus.