Is vitamin D deficiency in obese youth a risk factor for less weight loss during a weight loss program?

BACKGROUND: Vitamin D deficiency is common in obese adolescents and a risk factor for insulin resistance. We investigated if prevailing serum 25-OH vitamin D might predict the body fat loss in a group of obese adolescents undergoing a residential weight loss program. METHODS: In 92 (35 male) obese adolescents (aged 10.6-19 years) undergoing a residential weight loss program in Belgium, fasting serum 25-OH vitamin D (25-OH-D), insulin, glucose and lipid levels were measured and body composition was assessed by dual-energy X-ray absorptiometry (DXA). RESULTS: Baseline median (range) serum 25-OH-D level was 17.7 µg/L (3.8-41.8). In total, 55 adolescents had a serum 25-OH-D below 20 µg/L. In 31 adolescents with a low baseline 25-OH-D level, median increase in serum 25-OH-D was 2.4 µg/L (-4.2 to 7.2) after 10 months. This resulted in normal 25-OH-D levels in seven adolescents, whereas median BMI decreased with 1.0 SDS and body fat percentage diminished with 9.9%. Obese adolescents with or without a 25-OH-D level below or above 20 µg/L at baseline had similar changes in body weight, BMI SDS, body fat percentage and body fat mass at the end of the program. The change in serum 25-OH-D did not correlate with change in serum insulin, BMI SDS or body fat percentage and body fat mass. CONCLUSION: Vitamin D deficiency was present in 55 out of 92 obese adolescents at the start of the summer. Serum 25-OH-D concentration did not predict changes in body fat loss after a residential weight loss program.

Compound heterozygous mutations in the GNAS gene of a boy with morbid obesity, thyroid-stimulating hormone resistance, pseudohypoparathyroidism, and a prothrombotic state.

CONTEXT: Pseudohypoparathyroidism type Ia and pseudopseudohypoparathyroidism are characterized by Albright's hereditary osteodystrophy (AHO), respectively, with and without hormone resistance. Both clinical conditions result from decreased expression or function of the alpha-subunit of the stimulatory G protein (Gsalpha) of adenylyl cyclase due to heterozygous inactivating mutations in GNAS. Homozygous GNAS defects have not been described. OBJECTIVE: A genetic and functional GNAS study was undertaken in a boy with morbid obesity (body mass index Z-score of 5 at the age of 3 yr, with a body fat fraction of 40%, which is more than twice normal), TSH resistance, pseudohypoparathyroidism, and a prothrombotic state. RESULTS: The boy was found to be a first case with a compound heterozygous GNAS defect: a de novo R231C mutation on the paternal allele and on the other allele a maternally inherited unique combination of three C to T nucleotide substitutions in exon 7 (I185I), intron 7 (IVS7 + 31), and exon 13 (N371N) leading to aberrant splicing of GNAS. Platelets of this boy displayed a pronounced Gsalpha hypofunction and were spontaneously hyperreactive resulting in a prothrombotic state due to extremely low cAMP levels. CONCLUSION: This report expands the human GNAS genotype-phenotype spectrum to include compound heterozygosity and a prothrombotic state.

GNAS defects identified by stimulatory G protein alpha-subunit signalling studies in platelets.

CONTEXT: GNAS is an imprinted region that gives rise to several transcripts, antisense transcripts, and noncoding RNAs, including transcription of RNA encoding the alpha-subunit of the stimulatory G protein (Gsalpha). The complexity of the GNAS cluster results in ubiquitous genomic imprints, tissue-specific Gsalpha expression, and multiple genotype-phenotype relationships. Phenotypes resulting from genetic and epigenetic abnormalities of the GNAS region include Albright's hereditary osteodystrophy, pseudohypoparathyroidism types Ia (PHPIa) and Ib (PHPIb), and pseudopseudohypoparathyroidism (PPHP). OBJECTIVE: The aim was to study the complex GNAS pathology by a functional test as an alternative to the generally used but labor-intensive erythrocyte complementation assay. DESIGN AND PATIENTS: We report the first platelet-based diagnostic test for Gsalpha hypofunction, supported by clinical, biochemical, and molecular data for six patients with PHPIa or PPHP and nine patients with PHPIb. The platelet test is based on the inhibition of platelet aggregation by cAMP, produced after Gsalpha stimulation. RESULTS: Platelets are easily accessible, and platelet aggregation responses were found to reflect Gsalpha signaling defects in patients, in concordance with the patient's phenotype and genotype. Gsalpha hypofunction in PHPIa and PPHP patients with GNAS mutations was clearly detected by this method. Mildly decreased or normal Gsalpha function was detected in patients with PHPIb with either an overall or exon 1A-only epigenetic defect, respectively. Platelet Gsalpha expression was reduced in both PHPIb patient groups, whereas XLalphas was up-regulated only in PHPIb patients with the broad epigenetic defect. CONCLUSION: The platelet-based test is a novel tool for establishing the diagnosis of Gsalpha defects, which may otherwise be quite challenging.

Functional polymorphisms in the paternally expressed XLalphas and its cofactor ALEX decrease their mutual interaction and enhance receptor-mediated cAMP formation.

The paternally expressed extra-large stimulatory G protein gene (XLalphas) is a splice variant of the stimulatory G-protein gene (Gsalpha) consisting of XL-exon1 and exons 2-13 of Gsalpha. A second open reading frame (ORF) in XL-exon1, that completely overlaps the XL-domain ORF, encodes ALEX, which is translated from the XLalphas mRNA and binds the XL-domain of XLalphas. We previously demonstrated that a paternally inherited functional polymorphism in XL-exon1, consisting of a 36 bp insertion and two nucleotide substitutions, is associated with Gs hyperfunction in platelets, leading to an increased trauma-related bleeding tendency and is accompanied by neurological problems and brachydactyly in two families. Here, we describe eight additional patients with brachydactyly, who inherited the same XLalphas polymorphism paternally and who show Gs hyperfunction in their platelets and fibroblasts. All carriers also have an elongated ALEX protein, as a consequence of the paternally inherited insertion. The in vitro interaction between the two elongated XLalphas and ALEX proteins is markedly reduced. Moreover, XLalphas or ALEX can be co-immunoprecipitated with an antibody against either ALEX or XLalphas in platelets from a control but hardly from patients with the XLalphas/ALEX insertion. In contrast to the strong interaction between the two wild-type proteins, we suggest that this defective association results in unimpeded receptor-stimulated activation of XLalphas. The paternally inherited double XLalphas/ALEX functional polymorphism is also associated with elevated platelet membrane Gsalpha protein levels. Both phenomena contribute to increased Gs signaling in patients with platelet hypersensitivity towards Gs-agonists and may be accompanied by neurological problems or growth deficiency.