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Ghrelin, an endogenous ligand of the GH secretagogue receptor, stimulates appetite and causes obesity in animal models and in humans when given in pharmacologic doses. Prader-Willi Syndrome (PWS) is a genetic obesity syndrome characterized by GH deficiency and the onset of a voracious appetite and obesity in childhood. We, therefore, hypothesized that ghrelin levels may play a role in the expression of obesity in this syndrome. We measured fasting serum ghrelin levels in 13 PWS children with an average age of 9.5 yr (range, 5-15) and body mass index (BMI) of 31.3 kg/m2 (range, 22-46). The PWS group was compared with 4 control groups: 20 normal weight controls matched for age and sex, 17 obese children (OC), and 14 children with melanocortin-4 receptor mutations (MC4) matched for age, sex, and BMI, and a group of 3 children with leptin deficiency (OB). In non-PWS subjects, ghrelin levels were inversely correlated with age (r = 0.36, P = 0.007), insulin (r = 0.55, P < 0.001), and BMI (r = 0.62, P < 0.001), but not leptin. In children with PWS, fasting ghrelin concentrations were not significantly different compared with normal weight controls (mean +/- SD; 429 +/- 374 vs. 270 +/- 102 pmol/liter; P = 0.14). However, children with PWS did demonstrate higher fasting ghrelin concentrations (3- to 4-fold elevation) compared with all obese groups (OC, MC4, OB) (mean +/- SD; 429 +/- 374 vs. 139 +/- 70 pmol/liter; P < 0.001). In conclusion, ghrelin levels in children with PWS are significantly elevated (3- to 4-fold) compared with BMI-matched obese controls (OC, MC4, OB). Elevation of serum ghrelin levels to the degree documented in this study may play a role as an orexigenic factor driving the insatiable appetite and obesity found in PWS.

A family of p160 coactivators was initially identified based on ligand-dependent interactions with nuclear receptors and thought to function, in part, by recruiting CREB-binding protein͞ p300 to several classes of transcription factors. One of the p160 factors, p͞CIP͞AIB1, often amplified and overexpressed in breast cancer, also exhibits particularly strong interaction with CREBbinding protein͞p300. In this manuscript, we report that p͞CIP, which exhibits regulated transfer from cytoplasm to nucleus, is required for normal somatic growth from embryonic day 13.5 through maturity. Our data suggest that a short stature phenotype of p͞CIP gene-deleted mice reflect both altered regulation of insulin-like growth factor-1 (IGF-1) gene expression in specific tissues and a cell-autonomous defect of response to IGF-1, including ineffective transcriptional activities by several classes of regulated transcription factors under specific conditions. The actions of p͞CIP are therefore required for full expression of a subset of genes critical for regulating physiological patterns of somatic growth in mammals. N uclear receptors comprise a family of transcription factors that regulate gene expression in a ligand-dependent manner and include receptors for steroid hormones, such as estrogen and glucocorticoid, receptors for nonsteroidal ligands, such as thyroid hormone receptor and retinoic acid receptor, as well as receptors that bind diverse products of lipid metabolism (reviewed in refs. 1-5). A combination of genetic, biochemical, and functional data suggests that many factors, including the BRG (Swi͞Snf) complex (6), CREB-binding protein (CBP)͞p300, p160 factors, p͞CAF, and the TRAP͞DRIP͞ARC (7, 8) complex are likely to be critical regulators for at least subsets of nuclear receptor-regulated genes (9-15). However, by the simple criteria of ligand-dependent binding and the ability to synergize on cotransfection assays, numerous additional proteins have been suggested to exert coactivator roles (4, 5).Proteins of approximately 160 kDa molecular mass were among the first factors identified that interact with nuclear receptor in a highly ligand-dependent manner both in solution (16, 17) and on DNA (18) and could themselves associate with CBP (11, 12). Expression cloning and yeast two-hybrid screening approaches led to the identification of three related genes that encode these p160 factors, referred to as SRC-1͞NCoA-1, TIF2͞GRIP-1͞NCoA2, and p͞CIP͞AIB1͞ACTR͞RAC3͞ TRAM-1 (11,(19)(20)(21)(22)(23)(24)(25). These factors bind to nuclear receptors by interactions of LXXLL motif-containing helices within the interaction domain formed by conserved residues in helix3 and helix12 of the liganded receptor (5).Members of the p160 family of nuclear receptor coactivators contain a highly conserved N-terminal bHLH-PAS domain that is also present in members of the Per͞Arnt͞Sim family of transcription factors and mediates protein-protein interactions. Although several lines of evidence support the idea that p160 factors play important roles as...