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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

GH secretory bursts are due to the combination of a pulsatile GRF release and a decreased Somatostatin secretion in hypophysial portal blood. In the intermediary periods, low plasma GH levels depend on the tonic release of hypothalamic Somatostatin. Experimental studies suggest that alterations in hypothalamic Somatostatin are involved in changes of GH secretion observed under physiological (foetal life, aging, stress), pharmacological (beta-blocking agents) and physiopathological conditions (starvation, obesity, diabetes). The Somatostatin analogue SMS 201-995 induces a long-lasting inhibition of GH secretion and may be useful in the treatment of acromegalic patients.
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PMID:[Somatostatin and regulation of the secretion of growth hormone]. 288 11

Somatostatin is present in the gastrointestinal tract in appreciable amounts. The highest concentrations of the polypeptide are found in the stomach, the upper small intestine, and the pancreas. Within the gastrointestinal tract, somatostatin inhibits various functions, including endocrine and exocrine secretion, motility, blood flow, absorption, and growth. The polypeptide regulates these functions by endocrine, paracrine, neurocrine or luminal mechanisms. Abnormalities of endogenous somatostatin have been implicated in several gastrointestinal disorders, including the somatostatinoma syndrome, antroduodenal D-cell hyperplasia, peptic ulcer, obesity, and liver cirrhosis. Because of its potent inhibitory effects, somatostatin or somatostatin-analogues have been used as therapeutic agents in various clinical conditions, such as upper gastrointestinal haemorrhage, endocrine pancreatic tumours, gastrointestinal and pancreatic fistulas, pancreatitis, secretory diarrhoea, and dumping syndrome. The recent availability of the synthetic long-acting somatostatin-analogue SMS 201-995 (Sandostatin) has greatly facilitated the therapeutical application of somatostatin-polypeptides.
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PMID:Clinical and pathophysiological aspects of somatostatin and the gastrointestinal tract. 289 34

Contiguous gene syndromes (CGS) are a group of disorders associated with chromosomal rearrangements of which the phenotype is thought to result from altered copy numbers of physically linked dosage-sensitive genes. Smith-Magenis syndrome (SMS) is a CGS associated with a deletion within band p11.2 of chromosome 17. Recently, patients harboring the predicted reciprocal duplication product [dup(17)(p11.2p11.2)] have been described as having a relatively mild phenotype. By chromosomal engineering, we created rearranged chromosomes carrying the deletion [Df(11)17] or duplication [Dp(11)17] of the syntenic region on mouse chromosome 11 that spans the genomic interval commonly deleted in SMS patients. Df(11)17/+ mice exhibit craniofacial abnormalities, seizures, marked obesity, and male-specific reduced fertility. Dp(11)17/+ animals are underweight and do not have seizures, craniofacial abnormalities, or reduced fertility. Examination of Df(11)17/Dp(11)17 animals suggests that most of the observed phenotypes result from gene dosage effects. Our murine models represent a powerful tool to analyze the consequences of gene dosage imbalance in this genomic interval and to investigate the molecular genetic bases of both SMS and dup(17)(p11.2p11.2).
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PMID:Modeling del(17)(p11.2p11.2) and dup(17)(p11.2p11.2) contiguous gene syndromes by chromosome engineering in mice: phenotypic consequences of gene dosage imbalance. 1272 22

Smith-Magenis syndrome (SMS) is a multiple congenital anomaly/mental retardation syndrome associated with del(17)(p11.2p11.2). The phenotype is variable even in patients with deletions of the same size. RAI1 has been recently suggested as a major gene for majority of the SMS phenotypes, but its role in the full spectrum of the phenotype remains unclear. Df(11)17/+ mice contain a heterozygous deletion in the mouse region syntenic to the SMS common deletion, and exhibit craniofacial abnormalities, seizures and marked obesity, partially reproducing the SMS phenotype. To further study the genetic basis for the phenotype, we constructed three lines of mice with smaller deletions [Df(11)17-1, Df(11)17-2 and Df(11)17-3] using retrovirus-mediated chromosome engineering to create nested deletions. Both craniofacial abnormalities and obesity have been observed, but the penetrance of the craniofacial phenotype was markedly reduced when compared with Df(11)17/+ mice. Overt seizures were not observed. Phenotypic variation has been observed in mice with the same deletion size in the same and in different genetic backgrounds, which may reflect the variation documented in the patients. These results indicate that the smaller deletions contain the gene(s), most likely Rai1, causing craniofacial abnormalities and obesity. However, genes or regulatory elements in the larger deletion, which are not located in the smaller deletions, as well as genes located elsewhere, also influence penetrance and expressivity of the phenotype. Our mouse models refined the genomic region important for a portion of the SMS phenotype and provided a basis for further molecular analysis of genes associated with SMS.
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PMID:Reduced penetrance of craniofacial anomalies as a function of deletion size and genetic background in a chromosome engineered partial mouse model for Smith-Magenis syndrome. 1545 75

Retinoic acid induced 1 (RAI1) is among the 20 genes identified in the critical region of Smith-Magenis syndrome (SMS), a genomic disorder with multiple congenital anomalies associated with a 3.7 Mb heterozygous deletion of 17p11.2. Heterozygous premature termination mutations in RAI1 have been identified recently in SMS patients without detectable deletions. To investigate Rai1 function, we generated a null allele in mice by gene targeting and simultaneously inserted a lacZ reporter gene into the Rai1 locus. X-gal staining of the Rai1(+/-) mice recapitulated the endogenous expression pattern of Rai1. The gene was predominantly expressed in the epithelial cells involved in organogenesis. Obesity and craniofacial abnormalities, which have been reported in SMS mouse models containing a heterozygous deletion of the syntenic SMS critical region, were observed in Rai1(+/-) mice. Thus, haploinsufficiency of Rai1 causes obesity and craniofacial abnormalities in mice. Interestingly, the penetrance of craniofacial anomalies is further reduced in Rai1(+/-) mice. Most homozygous mice died during gastrulation and organogenesis. The surviving Rai1(-/-) mice were growth retarded and displayed malformations in both the craniofacial and the axial skeleton. Using green fluorescence protein and GAL4 DNA binding domain fusions to Rai1, we showed that Rai1 is translocated to the nucleus and it has transactivation activity. Our data are consistent with Rai1 functioning as a transcriptional regulator, document that Rai1 haploinsufficiency is responsible for obesity and craniofacial phenotypes in mice with SMS deletions, and indicate Rai1 is important for embryonic and postnatal developments.
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PMID:Inactivation of Rai1 in mice recapitulates phenotypes observed in chromosome engineered mouse models for Smith-Magenis syndrome. 1574 53

Genomic disorders are conditions that result from DNA rearrangements, such as deletions or duplications. The identification of the dosage-sensitive gene(s) within the rearranged genomic interval is important for the elucidation of genes responsible for complex neurobehavioral phenotypes. Smith-Magenis syndrome is associated with a 3.7-Mb deletion in 17p11.2, and its clinical presentation is caused by retinoic acid inducible 1 (RAI1) haploinsufficiency. The reciprocal microduplication syndrome, dup(17)(p11.2p11.2), manifests several neurobehavioral abnormalities, but the responsible dosage-sensitive gene(s) remain undefined. We previously generated a mouse model for dup(17)(p11.2p11.2), Dp(11)17/+, that recapitulated most of the phenotypes observed in human patients. We have now analyzed compound heterozygous mice carrying a duplication [Dp(11)17] in one chromosome 11 along with a null allele of Rai1 in the other chromosome 11 homologue [Dp(11)17/Rai1(-) mice] in order to study the relationship between Rai1 gene copy number and the Dp(11)17/+ phenotypes. Normal disomic Rai1 gene dosage was sufficient to rescue the complex physical and behavioral phenotypes observed in Dp(11)17/+ mice, despite altered trisomic copy number of the other 18 genes present in the rearranged genomic interval. These data provide a model for variation in copy number of single genes that could influence common traits such as obesity and behavior.
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PMID:Rai1 duplication causes physical and behavioral phenotypes in a mouse model of dup(17)(p11.2p11.2). 1702 48

Smith-Magenis syndrome (SMS) is a multisystem disorder characterized by developmental delay and mental retardation, a distinctive behavioral phenotype, and sleep disturbance. We undertook a comprehensive meta-analysis to identify genotype-phenotype relationships to further understand the clinical variability and genetic factors involved in SMS. Clinical and molecular information on 105 patients with SMS was obtained through research protocols and a review of the literature and analyzed using Fisher's exact test with two-tailed p values. Several differences in these groups of patients were identified based on genotype and gender. Patients with RAI1 mutation were more likely to exhibit overeating, obesity, polyembolokoilamania, self-hugging, muscle cramping, and dry skin and less likely to have short stature, hearing loss, frequent ear infections, and heart defects when compared with patients with deletion, while a subset of small deletion cases with deletions spanning from TNFRSF13B to MFAP4 was less likely to exhibit brachycephaly, dental anomalies, iris abnormalities, head-banging, and hyperactivity. Significant differences between genders were also identified, with females more likely to have myopia, eating/appetite problems, cold hands and feet, and frustration with communication when compared with males. These results confirm previous findings and identify new genotype-phenotype associations including differences in the frequency of short stature, hearing loss, ear infections, obesity, overeating, heart defects, self-injury, self-hugging, dry skin, seizures, and hyperactivity among others based on genotype. Additional studies are required to further explore the relationships between genotype and phenotype and any potential discrepancies in health care and parental attitudes toward males and females with SMS.
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PMID:Gender, genotype, and phenotype differences in Smith-Magenis syndrome: a meta-analysis of 105 cases. 1753 3

The retinoic acid induced 1 gene (RAI1) is the primary causative gene for Smith-Magenis syndrome (SMS). Chromosomal deletion encompassing RAI1 or mutation in RAI1 is responsible for the majority of SMS features. Mouse models with targeted disruption of Rai1 have recapitulated overt SMS phenotypes, including craniofacial abnormalities, obesity, and neurobehavioral anomalies. Penetrance and expressivity of most phenotypes in mice were incomplete due to the mixed genetic background in which they were created. While increased penetrance of craniofacial phenotypes was observed in relatively homogeneous backgrounds, the effect of Rai1 haploinsufficiency on breeding outcome and fitness has not been studied. We analyzed mating results of Rai1+/- mice in a pure C57BL/6J background (>or=N10 generations). A significant distortion (P<0.05) of Mendelian transmission ratio with skewing against Rai1+/- mice was observed. Consequently, a decreased number of Rai1+/- pups and no Rai1-/- pups were obtained from all the breeding pairs. The decreased yield of Rai1+/- pups precluded penetrance studies of other phenotypes in these mice. However, when Rai1+/- alleles were transferred to a slightly variable (approximately 1% 129/approximately 99% C57BL/6J) genetic background expected numbers of Rai1+/- pups were obtained. Our results indicate that selection against Rai1-haploinsufficient alleles is governed primarily by modifier genes. Our data show that genetic background or modifier genes also significantly contribute to the severity of the phenotypes in SMS mouse models, mirroring the phenotypic variation observed in humans with Smith-Magenis syndrome and support the need for investigation of modifier loci for both single gene and complex genetic syndromes.
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PMID:Distorted Mendelian transmission as a function of genetic background in Rai1-haploinsufficient mice. 1911 76

Each human's genome is distinguished by extra and missing DNA that can be "benign" or powerfully impact everything from development to disease. In the case of genomic disorders DNA rearrangements, such as deletions or duplications, correlate with a clinical specific phenotype. The clinical presentations of genomic disorders were thought to result from altered gene copy number of physically linked dosage sensitive genes. Genomic disorders are frequent diseases (~1 per 1,000 births). Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS) are genomic disorders, associated with a deletion and a duplication, of 3.7 Mb respectively, within chromosome 17 band p11.2. This region includes 23 genes. Both syndromes have complex and distinctive phenotypes including multiple congenital and neurobehavioral abnormalities. Human chromosome 17p11.2 is syntenic to the 32-34 cM region of murine chromosome 11. The number and order of the genes are highly conserved. In this review, we will exemplify how genomic disorders can be modeled in mice and the advantages that such models can give in the study of genomic disorders in particular and gene copy number variation (CNV) in general. The contributions of the SMS and PTLS animal models in several aspects ranging from more specific ones, as the definition of the clinical aspects of the human clinical spectrum, the identification of dosage sensitive genes related to the human syndromes, to the more general contributions as the definition of genetic locus impacting obesity and behavior and the elucidation of general mechanisms related to the pathogenesis of gene CNV are discussed.
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PMID:Mouse models of genomic syndromes as tools for understanding the basis of complex traits: an example with the smith-magenis and the potocki-lupski syndromes. 1994 47

Smith-Magenis syndrome (SMS) is a genetic disorder caused by haploinsufficiency of the retinoic acid induced 1 (RAI1) gene. In addition to intellectual disabilities, behavioral abnormalities and sleep disturbances, a majority of children with SMS also have significant early-onset obesity. To study the role of RAI1 in obesity, we investigated the growth and obesity phenotype in a mouse model haploinsufficient for Rai1. Data show that Rai1(+/-) mice are hyperphagic, have an impaired satiety response and have altered abdominal and subcutaneous fat distribution, with Rai1(+/-) female mice having a higher proportion of abdominal fat when compared with wild-type female mice. Expression analyses revealed that Bdnf (brain-derived neurotrophic factor), a gene previously associated with hyperphagia and obesity, is downregulated in the Rai1(+/-) mouse hypothalamus, and reporter studies show that RAI1 directly regulates the expression of BDNF. Even though the Rai1(+/-) mice are significantly obese, serum analyses do not reveal any evidence of metabolic syndrome. Supporting these findings, a caregiver survey revealed that even though a high incidence of abdominal obesity is observed in females with SMS, they did not exhibit a higher incidence of indicators of metabolic syndrome above the general population. We conclude that Rai1 haploinsufficiency represents a single-gene model of obesity with hyperphagia, abnormal fat distribution and altered hypothalamic gene expression associated with satiety, food intake, behavior and obesity. Linking RAI1 and BDNF provides a more thorough understanding of the role of Rai1 in growth and obesity and insight into the complex pathogenicity of obesity, behavior and sex-specific differences in adiposity.
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PMID:Rai1 haploinsufficiency causes reduced Bdnf expression resulting in hyperphagia, obesity and altered fat distribution in mice and humans with no evidence of metabolic syndrome. 2066 24


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