leptin and Fibrous-Dysplasia--Polyostotic

Genetic factors are involved in the regulation of body weight and in determining individual responses to environmental factors such as diet and exercise. The identification and characterization of monogenic obesity syndromes have led to an improved understanding of the precise nature of the inherited component of severe obesity and has had undoubted medical benefits, whilst helping to dispel the notion that obesity represents an individual defect in behaviour with no biological basis. For individuals at highest risk of the complications of severe obesity, such findings provide a starting point for providing more rational mechanism-based therapies, as has successfully been achieved for one disorder, congenital leptin deficiency.

Topics: alpha-MSH; Bardet-Biedl Syndrome; Cell Cycle Proteins; Child; Child, Preschool; Endocrine System Diseases; Female; Fibrous Dysplasia, Polyostotic; Fragile X Syndrome; Humans; Leptin; Male; Membrane Proteins; Obesity; Prader-Willi Syndrome; Pro-Opiomelanocortin; Proprotein Convertase 1; Proteins; Receptor, Melanocortin, Type 4; Receptors, Cell Surface; Receptors, Leptin; Syndrome; Vesicular Transport Proteins; WAGR Syndrome

Deficiency of protein Gs (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 GNAS 1, the gene encoding the alpha-subunit of Gs. Obesity is a classical feature of patients with Gs 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 Gs 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 Gs-deficient children, as compared with controls. The degree of impairment of lipolysis was similar in Gs-deficient children who were only moderately overweight and in morbidly obese children. These findings extend the spectrum of hormonal resistance in Gs deficiency. Besides beta-adrenergic receptors, Gs protein itself should be examined as a possible step involved in the decreased lipolysis observed in common obesity.

Topics: Blood Glucose; Drug Resistance; Epinephrine; Fatty Acids, Nonesterified; Female; Fibrous Dysplasia, Polyostotic; Glycerol; GTP-Binding Protein alpha Subunits, Gs; Heart Rate; Humans; Insulin; Kinetics; Leptin; Lipolysis; Male; Mutation; Obesity