RESUMEN
Neuropeptide Y (NPY) appears to play a critical role in the integration of appetite and energy expenditure through NPY Y1 and Y5 receptor subtypes. Moreover, the NPY Y1 receptor is highly expressed on human adipocytes, where it inhibits lipolysis. The genes encoding these receptors are transcribed co-ordinately in opposite directions from a common promoter in a region of chromosome 4 that has been previously linked to triglyceride and small low-density lipoprotein (LDL) particle concentration. Therefore, the purpose of this investigation was to examine the relationship between polymorphisms in the genes encoding NPY Y1 and Y5 and the development of obesity and dyslipidemia. We screened the promoter and coding regions and identified four polymorphic variants. One of these, a cytosine to thymine (C-->T) substitution in the untranslated region between the genes for NPY Y1 and Y5 (allele frequency 0.11), was significantly associated with both lower fasting triglyceride level (152 vs 125 mg/dl), and higher high-density lipoprotein (HDL) concentrations (49 vs 45 mg/dl) (p < 0.01) in 306 obese subjects. Given the stimulatory effect of NPY on adipocyte lipoprotein lipase (LPL) activity, and the lack of association of other polymorphisms with serum lipid levels, we hypothesize that this is a gain-in-function polymorphism.
Asunto(s)
HDL-Colesterol/sangre , Receptores de Neuropéptido Y/genética , Triglicéridos/sangre , Adulto , Femenino , Haplotipos , Humanos , Masculino , Obesidad/genética , Polimorfismo GenéticoRESUMEN
OBJECTIVE: Previous studies have reported modest associations between measures of obesity and the Trp64-Arg variant of the beta3-adrenergic receptor (ADRbeta3) and the Pro12Ala variant of the peronisome proliferator-activated receptor (PPAR)-gamma2. We hypothesized that these single gene variants may mark mutations that act through convergent pathways to produce synergistic effects on obesity. RESEARCH DESIGN AND METHODS: The sample included 453 subjects from 10 large Mexican-American families participating in the population-based San Antonio Family Heart Study. The effects of each gene variant singly and jointly were estimated as fixed effects using the measured genotype approach framework. Analyses were conditioned on the pedigree structures to account for the correlations among family members. Statistical significance was evaluated by the likelihood ratio test with adjustment for age, sex and diabetes status. RESULTS: The allele frequencies for the ADRbeta3 Trp64Arg and PPARgamma2 Pro12Ala variants were 18 and 12%, respectively. The ADRbeta3 variant was not significantly associated with any of the obesity-related traits, but subjects with the PPAR-gamma2 variant (n = 98) had significantly higher levels of lasting insulin (P = 0.03), leptin (P = 0.009), and waist circumference (P = 0.03) than those without. Subjects with the gene variants (n = 32) had significantly higher BMI, insulin, and leprtin levels than those with only the PPARgamma2 variant (n = 66) (P for interaction: 0.04, 0.02, and 0.01 for BMI, fasting insulin, and leptin, respectively). CONCLUSIONS: Our results suggest that epistatic models with genes that have modest individual effects may be useful in understanding the genetic underpinnings of typical obesity in humans.
Asunto(s)
Variación Genética , Obesidad/genética , Receptores Adrenérgicos beta 3/genética , Receptores Citoplasmáticos y Nucleares/genética , Factores de Transcripción/genética , Tejido Adiposo/anatomía & histología , Adulto , Sustitución de Aminoácidos , Arteriosclerosis/genética , Índice de Masa Corporal , ADN/sangre , Proteínas de Unión al ADN/genética , Femenino , Humanos , Insulina/sangre , Leptina/sangre , Linfocitos , Masculino , Americanos Mexicanos/genética , Obesidad/sangre , TexasAsunto(s)
Lipodistrofia/congénito , Lipodistrofia/dietoterapia , Adulto , Femenino , Humanos , Lamina Tipo A , Laminas , Lipodistrofia/genética , Proteínas Nucleares/genética , Polimorfismo Genético , Receptores Adrenérgicos beta/genética , Receptores Citoplasmáticos y Nucleares/genética , Factores de Transcripción/genéticaAsunto(s)
Obesidad/genética , Mutación Puntual , Receptores Citoplasmáticos y Nucleares/genética , Factores de Transcripción/genética , Adulto , Sustitución de Aminoácidos , Población Negra/genética , Femenino , Glutamina , Humanos , Indígenas Norteamericanos/genética , Masculino , Persona de Mediana Edad , Proteínas Nucleares/genética , Prolina , Estados Unidos , Población Blanca/genéticaRESUMEN
Peroxisome proliferator-activated receptors (PPAR) are transcription factors that regulate adipocyte differentiation and gene expression. We tested the hypothesis that the Pro12Ala variant of PPAR-gamma2 is associated with obesity and type 2 diabetes-related traits in 921 subjects from the San Antonio Family Heart Study. Subjects with at least one Ala allele (n=210) had significantly higher body mass index (P=0.015) and waist circumference (P=0.028) and significantly higher levels of serum leptin (P= 0.022) than those without the allele. Further studies will determine whether the Pro12Ala variant itself, or other genetic variation at PPAR-gamma, is responsible for this association with measures of obesity in Mexican Americans.
Asunto(s)
Americanos Mexicanos/genética , Obesidad/genética , Receptores Citoplasmáticos y Nucleares/genética , Factores de Transcripción/genética , Población Blanca/genética , Adulto , Índice de Masa Corporal , Femenino , Humanos , Leptina/genética , Masculino , TexasRESUMEN
OBJECTIVE: Peroxisome-proliferator-activated receptors gamma (PPAR gamma), is a key regulator of adipocyte differentiation and energy balance. Two naturally occurring mutations in the PPAR gamma gene, Pro115Gln and Pro12Ala, have recently been shown to impair the function of the PPAR gamma2 isoform of the receptor and to be associated with obesity or diabetes-related phenotypes in different populations. SUBJECTS: We studied the occurrence and possible associations of the Pro115Gln and Pro12Ala in the PPAR gamma2 gene with several clinical and metabolic phenotypes in three independent large populations of non-obese non-diabetic, type 2 diabetic, and morbidly obese French Caucasians. RESULTS: The Pro115Gln mutation was not found in any of the 1069 subjects screened including 626 obese patients. The frequency of the Pro12Ala mutation was similar in all groups (0.08, 0.11, 0.09) and was not associated with BMI or any of the clinical parameters tested. CONCLUSIONS: We conclude that the Pro115Gln mutation is not a frequent cause of morbid obesity in Caucasians and that the Pro12Ala mutation is not associated with clinically significant changes in these populations.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Mutación , Obesidad Mórbida/genética , Receptores Citoplasmáticos y Nucleares/genética , Factores de Transcripción/genética , Adulto , Anciano , Alanina , Femenino , Genotipo , Glutamina , Humanos , Masculino , Persona de Mediana Edad , ProlinaRESUMEN
OBJECTIVES: To test the hypothesis that the triad of hyperandrogenism, insulin resistance and acanthosis nigricans (HAIRAN syndrome) in the presence of obesity, also known as type C insulin resistance, is caused by mutations in the gene for peroxisome proliferator activated receptor gamma (PPARgamma), a receptor for the thiazolidinedione drugs that enhance sensitivity to insulin. To investigate possible correlations between mutations in PPARgamma and the degree of insulin resistance. DESIGN: A candidate gene approach to study the molecular basis for a syndrome of obesity; a comparison of genotype with in vivo phenotype. PATIENTS: Fifteen unrelated patients with HAIRAN syndrome and obesity. Controls for the gene analysis: 25 unrelated non-diabetic non-obese individuals. Controls for the metabolic studies: six unrelated patients with type 2 diabetes mellitus and nine unrelated non-diabetic non-obese individuals. MEASUREMENTS: Analysis of polymerase chain reaction (PCR) products of the 7 exons that constitute the entire coding region of both PPARgamma isoforms (PPARgamma1 and PPARgamma2) for single-stranded conformational polymorphisms (SSCP); in exons with variant patterns: restriction fragment length polymorphism (RFLP) analysis; and, where relevant, direct sequencing. Evaluation of insulin resistance using the insulin euglycaemic clamp technique. RESULTS: A synonymous substitution in codon 477 (CACHis --> CATHis) was found in one patient. A missense mutation in codon 12 of PPARgamma2 (CCAPro --> GCAAla) was found in another patient, but not in any of 25 non-diabetic, non-obese control individuals. The patient with the Pro12Ala variant had the highest steady state glucose infusion rate (SSGIR) and most marked suppression of hepatic glucose production rate (HGPR) of all of the patients studied. CONCLUSIONS: Mutations in the PPARgamma gene are unlikely to be major contributors to HAIRAN syndrome with obesity. The Pro12Ala variant may correlate with a lesser degree of insulin resistance in these patients.
Asunto(s)
Acantosis Nigricans/genética , Hiperandrogenismo/genética , Resistencia a la Insulina/genética , Obesidad/genética , Receptores Citoplasmáticos y Nucleares/genética , Factores de Transcripción/genética , Estudios de Casos y Controles , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/metabolismo , Femenino , Genotipo , Glucosa/metabolismo , Técnica de Clampeo de la Glucosa , Humanos , Hígado/metabolismo , Masculino , Obesidad/metabolismo , Fenotipo , Mutación Puntual , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo Conformacional Retorcido-Simple , Isoformas de Proteínas/genética , SíndromeRESUMEN
Diabetes mellitus is a large and growing health problem in the United States, and as such constitutes a target for many health initiatives. Exercise provides beneficial effects on excess weight, insulin resistance, and atherosclerosis, making it an important tool to mitigate diabetes symptoms and sequelae.
RESUMEN
To examine the role of the Pro12Ala variant of the human PPARgamma2 gene on adiposity and insulin resistance, we studied the effect of the variant on fat distribution assessed by CT scan, plasma glucose, and insulin levels during a 75g oral glucose load in 215 non-diabetic Japanese men. The allele frequency of the variant was 0. 03 in this population. There were no differences in body mass index (BMI), subcutaneous fat area (S), visceral fat area (V), V/S ratio, fasting plasma insulin levels, or insulin resistance index in homeostatic model assessment between 203 subjects who were homozygous for the wild-type Pro12 allele and 12 subjects with the variant Ala12 allele (11 heterozygotes and one homozygote). These data suggest that the Pro12Ala variant is not a major contributor to adiposity, fat distribution, or insulin resistance in Japanese men.
Asunto(s)
Tejido Adiposo/metabolismo , Alanina/genética , Sustitución de Aminoácidos/genética , Grasas/metabolismo , Resistencia a la Insulina/genética , Proteínas Nucleares/genética , Prolina/genética , Receptores Citoplasmáticos y Nucleares/genética , Factores de Transcripción/genética , Adulto , Anciano , Presión Sanguínea/genética , Índice de Masa Corporal , Variación Genética , Humanos , Japón , Lípidos/sangre , Masculino , Persona de Mediana EdadAsunto(s)
Mutación , Obesidad/metabolismo , Prolina/genética , Receptores Citoplasmáticos y Nucleares/genética , Factores de Transcripción/genética , Tejido Adiposo/metabolismo , Animales , Estudios de Cohortes , Humanos , Ratones , Músculo Esquelético/metabolismo , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Estudios Prospectivos , ARN Mensajero/metabolismoRESUMEN
We determined the chromosomal localization and partial genomic structure of the coding region of the human PPAR gamma gene (hPPAR gamma), a nuclear receptor important for adipocyte differentiation and function. Sequence analysis and long PCR of human genomic DNA with primers that span putative introns revealed that intron positions and sizes of hPPAR gamma are similar to those previously determined for the mouse PPAR gamma gene[13]. Fluorescent in situ hybridization localized hPPAR gamma to chromosome 3, band 3p25. Radiation hybrid mapping with two independent primer pairs was consistent with hPPAR gamma being within 1.5 Mb of marker D3S1263 on 3p25-p24.2. These sequences of the intron/exon junctions of the 6 coding exons shared by hPPAR gamma 1 and hPPAR gamma 2 will facilitate screening for possible mutations. Furthermore, D3S1263 is a suitable polymorphic marker for linkage analysis to evaluate PPAR gamma's potential contribution to genetic susceptibility to obesity, lipoatrophy, insulin resistance, and diabetes.
Asunto(s)
Mapeo Cromosómico , Cromosomas Humanos Par 3/genética , Receptores Citoplasmáticos y Nucleares/genética , Factores de Transcripción/genética , Tejido Adiposo/metabolismo , Animales , Secuencia de Bases , Bandeo Cromosómico , Clonación Molecular , ADN/genética , Cartilla de ADN/genética , Exones , Ligamiento Genético , Marcadores Genéticos , Humanos , Intrones , Ratones , Sondas de Oligonucleótidos/genética , Reacción en Cadena de la Polimerasa , Polimorfismo GenéticoRESUMEN
Peroxisome proliferator activated receptor-gamma (PPAR gamma) is a nuclear receptor that regulates adipocyte differentiation, and possibly lipid metabolism and insulin sensitivity. As such, PPAR gamma is a promising candidate gene for several human disorders including obesity and type 2 diabetes mellitus. Screening for mutations in the entire coding region of the PPAR gamma gene (both gamma 1 and gamma 2 isoforms) was performed with DNA of 26 diabetic Caucasians with or without obesity. Two base substitutions were identified: a silent mutation at nucleotide 1431 (CACHis-->CATHis) and a missense mutation (CCGPro-->GCGAla) at codon 12 of PPAR gamma 2. The allele frequency of the Pro12Ala PPAR gamma 2 variant was 0.12 in Caucasian Americans, 0.10 in Mexican Americans, 0.08 in Samoans, 0.03 in African Americans, 0.02 in Nauruans, and 0.01 in Chinese. We conclude that the Pro12Ala PPAR gamma 2 gene variant is present in diverse populations. Further studies of the Pro12Ala variant will determine its relevance to obesity, insulin resistance, and type 2 diabetes.
Asunto(s)
Diabetes Mellitus Tipo 2/genética , Mutación , Receptores Citoplasmáticos y Nucleares/genética , Factores de Transcripción/genética , Población Blanca/genética , Adulto , Anciano , Anciano de 80 o más Años , Secuencia de Aminoácidos , Secuencia de Bases , Clonación Molecular , Exones , Femenino , Frecuencia de los Genes , Pruebas Genéticas/métodos , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Obesidad/genética , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Polimorfismo Conformacional Retorcido-Simple , Análisis de Secuencia de ADN , Estados UnidosAsunto(s)
Directivas Anticipadas/legislación & jurisprudencia , Enfermedad de Alzheimer/psicología , Consentimiento Informado/legislación & jurisprudencia , Anciano , Concienciación , Toma de Decisiones , Femenino , Humanos , Cuidados para Prolongación de la Vida/legislación & jurisprudencia , Cuidados para Prolongación de la Vida/psicología , Masculino , Recuerdo Mental , Escala del Estado Mental , Autonomía Personal , Proyectos Piloto , Medición de RiesgoRESUMEN
Stool specimens obtained from 77 residents of a nursing home were analysed to determine the relationship between colonisation with digoxin-reducing strains of Eubacterium lentum and infection with Clostridium difficile. Patients were categorised according to previous antibiotic treatment, prescription of enteral feedings, and pattern of bowel habits. Colonisation with digoxin-reducing E. lentum was less common in subjects infected with C. difficile, in those treated with antibiotics previously, and in those prescribed enteral feedings. Normal bowel habits were more common in those without C. difficile. The lowest incidence of diarrhoea was seen in patients without C. difficile who were colonised with digoxin-reducing species. This study establishes an inverse relationship between the presence of C. difficile and E. lentum that reduce digoxin which is related to previous treatment with antibiotics and prescription of enteral feedings. Bacterial markers may prove to be a useful tool for predicting clinical disturbances in bowel function.