Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0028754 (obesity)
 124,988 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effects of obesity and sex on hepatic insulin metabolism were evaluated in the SHR/Mcc-cp rat. During in situ liver perfusion, insulin clearance rate (CLR) expressed per gram of liver tissue was reduced by 58 and 68% in obese females and males, respectively, compared with lean controls. Male sex resulted in CLR reductions of 46% in lean and 59% in obese animals. Obesity resulted in 50% reduction of insulin-receptor binding to isolated hepatocytes. In both lean and obese animals, male sex also resulted in a decrease of approximately 34% in insulin binding. Scatchard plots indicated that the reduction in insulin binding was primarily due to a decrease in number of cell surface receptors. Receptor-mediated insulin degradation was 40% less in obese than lean animals. Male sex also resulted in 27% less insulin degradation relative to females. Receptor-mediated insulin partitioning between four compartments (cell surface bound, internalized and/or cryptic, degraded, and dissociated or released intact), expressed as a percentage of the initial membrane-bound hormone, did not differ between the animal groups. Thus, male sex and obesity are independently and additively associated with a reduction in hepatic insulin clearance and a decrease in the number of cell surface insulin receptors with a proportional decrease insulin compartmentalization and degradation. This mechanism may partly account for the synergistic effects of male sex and obesity on the degree of hyperinsulinemia and insulin resistance and the predisposition to diabetes.
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PMID:Synergistic effects of male sex and obesity on hepatic insulin dynamics in SHR/Mcc-cp rat. 219 85

The physiological control of adrenal androgen secretion has not been definitively established. However, there is evidence to suggest that a dexamethasone-suppressible factor other than ACTH may have a specific role to play. The majority of patients with idiopathic hirsutism (hirsutism associated with regular menstruation) have findings suggestive of adrenal androgen excess, including enhanced androgen responsiveness following administration of metyrapone, and respond to treatment with dexamethasone, 0.5 mg given each night. Patients with idiopathic hirsutism have elevated androgens but normal oestrogen and gonadotrophin levels. In contrast, while patients with polycystic ovary syndrome (PCOS) also demonstrate evidence of adrenal androgen excess, these patients have elevated oestrone levels and gonadotrophin secretion is abnormal. Approximately 50% of patients with PCOS treated with dexamethasone resume regular menstruation. Oestrone excess appears to be primary to the abnormal gonadotrophin secretion and to the development of PCOS. In non-obese patients with PCOS elevated oestrone appears to occur as a consequence of the availability of the excessive amounts of its immediate precursor, androstenedione, an androgen mainly of adrenal origin. Androstenedione is converted to oestrone in fat. Obese amenorrhoeic subjects have normal androstenedione values but elevated oestrone levels with abnormal gonadotrophin secretion as seen in PCOS. These findings indicate that abnormal gonadotrophin secretion is associated with elevated oestrone levels whether these occur as a consequence of excessive adrenal androgen secretion, or the excessive conversion of normal amounts of available androstenedione. Patients with idiopathic hirsutism and elevated androstenedione levels but normal oestrone values appeared to be protected against the development of PCOS by relatively poor conversion of androstenedione to oestrone. It is likely, therefore, that if patients with idiopathic hirsutism gain additional adipose tissue, elevated oestrone levels will result and PCOS will develop. These observations explain the frequent association of PCOS and obesity. There is a close clinical association between elevated androgen levels and hirsutism and between elevated oestrone levels and menstrual disturbances. However, some patients with amenorrhoea but without hirsutism may demonstrate marked elevations of androgens and oestrone, the correction of which leads to the resumption of regular ovulation. This presentation, 'amenorrhoea with cryptic hyperandrogenaemia', is probably explained by diminished sensitivity of androgen receptors.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:The adrenal cortex and virilization. 300 82

The agouti gene normally confers the wild-type coat color of mice. Dominant mutations at the agouti locus result in a pleiotropic syndrome that is characterized by excessive amounts of yellow pigment in the coat, obesity, a non-insulin-dependent diabetic-like condition, and the propensity to form a variety of tumors. Here, we describe a new dominant mutation at the agouti locus in which an intracisternal A-particle (IAP) has integrated in an antisense orientation immediately 5' of the first coding exon of the gene. This mutation, which we have named Aiapy, results in the ectopic expression of the agouti gene through the utilization of a cryptic promoter within the IAP 5' long terminal repeat (LTR). The coat color of Aiapy/-mice ranges from solid yellow to a pigment pattern that is similar to wild type (pseudoagouti), and the expressivity of this mutant phenotype varies with parental inheritance. Those offspring with a yellow coat ectopically express agouti mRNA at high levels and exhibit marked obesity, whereas pseudoagouti mice express agouti mRNA at a very low level and their weights do not differ from wild-type littermates. Data are presented to show that the differential expressivity of the Aiapy allele is correlated with the methylation status of the inserted IAP 5' LTR. These data further support the hypothesis that in dominant yellow mutations at the agouti locus, it is the ubiquitous expression of the wild-type agouti coding sequence that is responsible for the yellow coat color, obesity, diabetes, and tumorigenesis.
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PMID:Differential expression of a new dominant agouti allele (Aiapy) is correlated with methylation state and is influenced by parental lineage. 792 45

Interpretation of a complex chromosome rearrangement (CCR) using only G-band analysis is difficult and potentially inaccurate. We present two patients with de novo, partially cryptic, CCRs that illustrate both the value and limitations of using fluorescence in situ hybridization (FISH) whole chromosome paint probes to characterize these types of rearrangements. In a patient referred because of features of Townes-Brocks syndrome, G-band analysis revealed an unbalanced CCR involving 3 chromosomes (2,11 and 16) and at least 4 breakpoints. A more complex rearrangement involving two cryptic insertions and at least 6 breakpoints, however, was detected using whole chromosome paint probes specific for the 3 chromosomes involved in the rearrangement. In this case, FISH studies were essential for accurate characterization of this patient's rearrangement. In a second patient, G-band analysis revealed that a 12-year-old male with obesity, small genitalia, attention deficit disorder, learning disabilities, and behavior problems, carried a CCR involving 4 chromosomes (3, 5, 10 and 13) with 6 breakpoints. This rearrangement seemed unbalanced, with missing terminal 3p26. 2-pter material. Our G-band interpretation of this karyotype was confirmed by FISH using whole chromosome paint probes specific for the involved chromosomes. Although no evidence of the "missing" 3pter material was observed using a chromosome 3 paint, FISH analysis using a chromosome 3p unique telomere probe identified telomeric 3p material on the distal long arm of the derivative 10 chromosome. This case illustrates the limited value of painting probes to detect small rearrangements, especially those involving terminal chromosome regions.
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PMID:Usefulness and limitations of FISH to characterize partially cryptic complex chromosome rearrangements. 1107 91

The objective of the current study was to examine the potential impact of a cryptic trinucleotide repeat polymorphism in exon 3 of proopiomelanocortin (POMC) on serum leptin levels and salivary cortisol, as well as obesity and estimates of insulin, glucose, and lipid metabolism in 284 unrelated Swedish men born in 1944. Moreover, we examined if a single nucleotide polymorphism (SNP) (C-->T) in exon 3 was associated with these characteristics. The amplification of the microsatellite locus yielded a 155-bp fragment and a fragment with one additional copy of the 9-bp repeat unit GGCAGCAGC (164 bp). The allelic frequencies were 0.96 and 0.04, respectively. Tests for differences in phenotype showed that subjects with the longer polymerase chain reaction (PCR) repeat product (n = 21) had significantly higher serum leptin concentrations (P =.024) compared with subjects with the shorter PCR product (n = 230). Salivary cortisol levels, as well as obesity and its related metabolic perturbations, were the same across the POMC genotypes. In conclusion, a microsatellite polymorphism in exon 3 of POMC is associated with elevated serum leptin levels. This association might reflect variations in melanocortin expression and/or activity, because exon 3 contains, among others, the coding sequences for melanocortins.
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PMID:Polymorphisms in exon 3 of the proopiomelanocortin gene in relation to serum leptin, salivary cortisol, and obesity in Swedish men. 1197 99

We report on two brothers with moderate-to-severe mental retardation, severe macrocephaly, obesity, characteristic face, big hands and feet, advanced bone age and brain abnormalities, including frontal cortical atrophy. These two boys resembled the two brothers described by , two maternal cousins subsequently reported by and a Brazilian boy described by . Upon further investigation, we detected a cryptic subtelomeric deletion of chromosome region 22q13, not present in either parent and probably due to a maternal germinal mosaicism. Thus, we describe the first familial case of 22q13 deletion and recommend that patients with a phenotype suggestive of the so-called Clark-Baraitser syndrome be tested for submicroscopic 22qter deletion.
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PMID:Two brothers with 22q13 deletion syndrome and features suggestive of the Clark-Baraitser syndrome. 1593 Sep 1

Cryptogenic cirrhosis (CC) is diagnosed in 5-30% of cirrhotic patients overall and 7% of patients who undergo liver transplantation for cirrhosis. In our series of patients transplanted for CC, pre-transplant clinical and histological data and the post-transplant course were reexamined in an attempt to identify the aetiology. Among the 881 patients transplanted in our centre between 1987 and 2000, 28 patients with a median age of 46 yr (range: 18-69) at transplantation were initially classified as having CC. Two patients were excluded because of intense ischaemic lesions caused by chemoembolization prevented histological analysis of the native liver (n = 1) and because of cryptic HBV infection (n = 1). Among the remaining 26 patients, four groups were individualized: (i) patients with chronic inflammatory liver disease with autoimmune features (n = 14, 54%); (ii) patients with features suggestive of non-alcoholic fatty liver disease (n = 3, 11.5%); (iii); patients with incomplete septal cirrhosis (ISC) and vascular liver disease (n = 3), and (iv) patients with unresolved CC (n = 6, 23%). In the autoimmune liver disease group, the median International Autoimmune Hepatitis score was 12.5 (range: 11-19) after reevaluation and review of the post-transplantation course was helpful to confirm the diagnosis with the occurrence of active graft hepatitis in nine patients, with autoantibodies in five patients. The vascular group was characterized by lesions of obliterative portal venopathy and ISC in all native livers. Diagnosis of NAFLD was based on the clinical background of obesity and/or type 2 diabetes and the presence of steatosis or steatohepatitis in native livers and graft biopsies. A definite aetiological diagnosis can be achieved in the majority of patients initially diagnosed with CC. Autoimmune liver disease emerged as the main aetiology (14 of 26 patients, 54%) and frequently recurred on the grafted liver (nine cases). In all cases a precise diagnosis is obviously of practical interest for better management of post-transplant survey and treatment.
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PMID:Could post-liver transplantation course be helpful for the diagnosis of so called cryptogenic cirrhosis? 1710 Jul 32

Screening of a large series of patients with unexplained mental retardation with a 1 Mb BAC array resulted in the detection of several cryptic chromosomal imbalances. In this paper we present the findings of array CGH screening in a 14-year-old boy with the brachytelephalangic type of chondrodysplasia punctata, mental retardation and obesity. On several occasions, cytogenetic analysis of this boy revealed a normal karyotype. Subsequent screening with array CGH resulted in the detection of a distal 9p trisomy and distal Xp nullisomy caused by an unbalanced X;9 translocation: 46,Y,der(X)t(X;9)(p22.32;p23). The identification of this de novo chromosomal rearrangement not only made accurate genetic counselling possible but also explained most of the phenotypic abnormalities observed in this patient. This study confirms the power of array CGH in the detection of subtle or submicroscopic chromosomal changes.
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PMID:Identification of an unbalanced X-autosome translocation by array CGH in a boy with a syndromic form of chondrodysplasia punctata brachytelephalangic type. 1617 25

Predisposition to type 1 diabetes and juvenile obesity is influenced by the susceptibility locus IDDM2 that includes the insulin gene (INS). Although the risk conferred by IDDM2 has been attributed to a minisatellite upstream of INS, intragenic variants have not been ruled out. We examined whether INS polymorphisms affect pre-mRNA splicing and proinsulin secretion using minigene reporter assays. We show that IVS1-6A/T (-23HphI+/-) is a key INS variant that influences alternative splicing of intron 1 through differential recognition of its 3' splice site. The A allele resulted in an increased production of mature transcripts with a long 5' leader in several cell lines, and the extended mRNAs generated more proinsulin in culture supernatants than natural transcripts. The longer mRNAs were significantly overrepresented among beta-cell-expressed sequenced tags containing the A allele as compared with those with T alleles. In addition, we show that a rare insertion/deletion polymorphism IVS1+5insTTGC (IVS-69), which is exclusively present in Africans, activated a downstream cryptic 5' splice site, extending the 5' leader by 30 bp. These results indicate that -23HphI and IVS-69 are the most important INS variants affecting pre-mRNA splicing and suggest that -23HphI+/- is a common functional single nucleotide polymorphism at IDDM2.
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PMID:Variants in the human insulin gene that affect pre-mRNA splicing: is -23HphI a functional single nucleotide polymorphism at IDDM2? 1638 May 1

Osteoarthritis (OA) is the most common form of arthritis worldwide. In this condition, damage to the extracellular matrix (ECM) of cartilage occurs, resulting in joint destruction. Factors mediating cartilage damage include mechanical injury, cytokine and superoxide release on a background of genetic susceptibility and obesity. Studies of arthritic cartilage show increased production of ECM molecules including type II collagen, cartilage oligomeric matrix protein, fibronectin (FN) and fibromodulin. Recent reports suggest that ECM proteins may become endogenous catabolic factors during joint damage. Activation of pro-inflammatory pathways by ECM proteins has led to their description as damage-associated molecular patterns (DAMPs). The ECM proteins involved include fibromodulin, which activates the complement pathway and may promote the persistence of joint inflammation. Fragmentation of type II collagen, FN and hyaluronan reveals cryptic epitopes that stimulate proteolytic enzymes including matrix metalloproteinases and aggrecanases (ADAMTSs - a disintegrin and metalloproteinase with thrombospondin type 1 motifs). Proteolytic fragments also stimulate the release of nitric oxide, chemokines and cytokines and activation of the MAP kinases. Reports are emerging that the receptors for the fragments described involve interaction with integrins and toll-like receptors. In this review the contribution of endogenous ECM molecules to joint destruction will be discussed. A deeper understanding of the pathways stimulated by endogenous ligands could offer potential avenues for novel therapies in the future.
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PMID:Analysing the role of endogenous matrix molecules in the development of osteoarthritis. 1976 1


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