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Resistance to the Lipolytic Action of Epinephrine: A New Feature of Protein G_s Deficiency

Department of Pediatric Endocrinology and INSERM U342 (J.C.C., C.L.S, L.C., J.L.C., P.B.), and CNRS UPR 1524 (L.C., M.G.), Hôpital Saint Vincent de Paul, 75014 Paris, France; Department of Pediatrics (E.M.), Hôpital Charles Nicolle, 76000 Rouen, France; and Centre de Recherche (P.A.), Groupe LIPHA, 91380 Chilly-Mazarin, France

Address correspondence and requests for reprints to: Dr. Jean-Claude Carel, INSERM U342, Hôpital Saint Vincent de Paul 82 av Denfert Rochereau, 75014 Paris, France. E-mail: carel{at}cochin.inserm.fr

Deficiency of protein G_s (Gs; OMIM no.103580), the stimulatory regulator of adenylyl cyclase, is associated with resistance to PTH and other hormones, sc calcifications, short stature, and skeletal defects (Albright’s hereditary osteodystrophy). It is caused by heterozygous loss of function mutations in GNAS1, the gene encoding the -subunit of G_s. Obesity is a classical feature of patients with G_s deficiency, but the mechanism leading to fat accumulation has not been elucidated. We measured glycerol flux, using a nonradioactive tracer dilution approach, to analyze the lipolytic response to epinephrine in 6 patients with G_s deficiency and PTH resistance and compared it to six age-matched normal controls and nine massively obese children. Basal glycerol production was reduced by 50%, and lipolytic response to epinephrine was reduced by 67%, in G_s-deficient children, as compared with controls. The degree of impairment of lipolysis was similar in G_s-deficient children who were only moderately overweight and in morbidly obese children. These findings extend the spectrum of hormonal resistance in G_s deficiency. Besides ß-adrenergic receptors, G_s protein itself should be examined as a possible step involved in the decreased lipolysis observed in common obesity.

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