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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...

The identification of a second case of severe growth failure associated with STAT5b mutation implicates a unique and critical role for STAT5b in GH stimulation of IGF-I gene expression and statural growth.

ALS is critical for maintaining normal serum concentrations of IGF-I and IGFBP-3, most likely by prolonging the half-lives of both proteins. ALS deficiency can be associated with moderate growth failure, but in this patient, the onset and progression of puberty appear to be normal. Altogether the results support a modest role for the ternary complex in the regulation of stature.

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IGF-binding protein (IGFBP)-related protein 1 (IGFBP-rP1) has been shown to bind both IGFs and insulin, albeit with low affinity, and to inhibit insulin signaling. We hypothesized that IGFBP-rP1 is associated with insulin resistance and components of the IGF system in humans. To this aim, a cross-sectional study was conducted in 113 nondiabetic and 43 type 2 diabetic men. Insulin sensitivity (insulin sensitivity index [S i ] from intravenous glucose tolerance tests in nondiabetic subjects, or the rate constant for disappearance of glucose [K ITT ] from insulin tolerance tests in type 2 diabetic subjects), circulating IGFBP-rP1 (from enzyme-linked immunosorbent assay), adiponectin (from radioimmunoassay), C-reactive protein (CRP; from immunoturbidimetry), soluble tumor necrosis factor receptor 2 (sTNFR2; from enzyme-amplified sensitivity immunoassay), and IGF system parameters (IGF-I, free IGF-I, and IGFBP-1 from immunoradiometric assay) were assessed in all subjects. Among nondiabetic men, those in the highest quartile for circulating IGFBP-rP1 exhibited decreased S i and adiponectin (both P < 0.01) as well as increased CRP and sTNFR2 (both P < 0.05). Circulating IGFBP-rP1 was also found to be increased in previously undiagnosed type 2 diabetic patients (P ‫؍‬ 0.01) but not in known type 2 diabetic patients receiving pharmacological therapy. Although no changes in IGF system components were evident by IGFBP-rP1 quartiles in nondiabetic subjects, independent positive associations of IGFBP-rP1 with circulating fasting IGFBP-1 were evident after adjustment for insulin resistance parameters in both nondiabetic and type 2 diabetic subjects, with IGFBP-rP1 explaining 2 and 11% of IGFBP-1 variance, respectively. In additional multivariate analyses, S i , sTNFR2, and age stood as independent predictive variables of IGFBP-rP1 (together explaining 18% of its variance) in nondiabetic subjects, and BMI became the only independent predictive variable of IGFBP-rP1 (explaining 26% of its variance) in type 2 diabetic men. These findings show for the first time that circulating IGFBP-rP1 is increased with insulin resistance, and they also suggest novel interactions between IGFBP-rP1 and the IGF system in humans.