Resistance to the lipolytic action of epinephrine: A new feature of protein G(s) deficiency

Deficiency of protein G(s) (Gs; OMIM no.103580), the stimulatory regulator of adenylyl cyclase, is associated with resistance to PTH and other hormone s, sc calcifications, short stature, and skeletal defects (Albright's hered itary osteodystrophy). It is caused by heterozygous loss of function mutati ons in GNAS1, the gene encoding the alpha-subunit of G(s). Obesity is a cla ssical feature of patients with G(s) deficiency, but the mechanism leading to fat accumulation has not been elucidated. We measured glycerol flux, usi ng a nonradioactive tracer dilution approach, to analyze the lipolytic resp onse to epinephrine in 6 patients with G(s) deficiency and PTH resistance a nd compared it to six age-matched normal controls and nine massively obese children. Basal glycerol production was reduced by 50%, and lipolytic respo nse to epinephrine was reduced by 67%, in G(s)-deficient children, as compa red with controls. The degree of impairment of lipolysis was similar in G(s )-deficient children who were only moderately overweight and in morbidly ob ese children. These findings extend the spectrum of hormonal resistance in G(s) deficiency. Besides beta-adrenergic receptors, G(s) protein itself sho uld be examined as a possible step involved in the decreased lipolysis obse rved in common obesity.