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A re-examination of the Ghrelin and Ghrelin receptor genesSeim, Inge January 2009 (has links)
The last few years have seen dramatic advances in genomics, including the discovery of a large number of non-coding and antisense transcripts. This has revolutionised our understanding of multifaceted transcript structures found within gene loci and their roles in the regulation of development, neurogenesis and other complex processes. The recent and continuing surge of knowledge has prompted researchers to reassess and further dissect gene loci. The ghrelin gene (GHRL) gives rise to preproghrelin, which in turn produces ghrelin, a 28 amino acid peptide hormone that acts via the ghrelin receptor (growth hormone secretagogue receptor/GHSR 1a). Ghrelin has many important physiological and pathophysiological roles, including the stimulation of growth hormone (GH) release, appetite regulation, and cancer development. A truncated receptor splice variant, GHSR 1b, does not bind ghrelin, but dimerises with GHSR 1a, and may act as a dominant negative receptor. The gene products of ghrelin and its receptor are frequently overexpressed in human cancer While it is well known that the ghrelin axis (ghrelin and its receptor) plays a range of important functional roles, little is known about the molecular structure and regulation of the ghrelin gene (GHRL) and ghrelin receptor gene (GHSR). This thesis reports the re-annotation of the ghrelin gene, discovery of alternative 5’ exons and transcription start sites, as well as the description of a number of novel splice variants, including isoforms with a putative signal peptide. We also describe the discovery and characterisation of a ghrelin antisense gene (GHRLOS), and the discovery and expression of a ghrelin receptor (growth hormone secretagogue receptor/GHSR) antisense gene (GHSR-OS). We have identified numerous ghrelin-derived transcripts, including variants with extended 5' untranslated regions and putative secreted obestatin and C-ghrelin transcripts. These transcripts initiate from novel first exons, exon -1, exon 0 and a 5' extended 1, with multiple transcription start sites. We used comparative genomics to identify, and RT-PCR to experimentally verify, that the proximal exon 0 and 5' extended exon 1 are transcribed in the mouse ghrelin gene, which suggests the mouse and human proximal first exon architecture is conserved. We have identified numerous novel antisense transcripts in the ghrelin locus. A candidate non-coding endogenous natural antisense gene (GHRLOS) was cloned and demonstrates very low expression levels in the stomach and high levels in the thymus, testis and brain - all major tissues of non-coding RNA expression. Next, we examined if transcription occurs in the antisense orientation to the ghrelin receptor gene, GHSR. A novel gene (GHSR-OS) on the opposite strand of intron 1 of the GHSR gene was identified and characterised using strand-specific RT-PCR and rapid amplification of cDNA ends (RACE). GHSR-OS is differentially expressed and a candidate non-coding RNA gene. In summary, this study has characterised the ghrelin and ghrelin receptor loci and demonstrated natural antisense transcripts to ghrelin and its receptor. Our preliminary work shows that the ghrelin axis generates a broad and complex transcriptional repertoire. This study provides the basis for detailed functional studies of the the ghrelin and GHSR loci and future studies will be needed to further unravel the function, diagnostic and therapeutic potential of the ghrelin axis.
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Relação de polimorfismos nos genes da perilipina 1, visfatina, resistina e grelina com a resposta a um programa de orientação nutricional para a redução de peso corporal / Relationship of polymorphisms in the perilipine 1, visfatin, resistin and ghrelin genes with the response to the nutritional orientation program for the reduction of body weightSantos, Marina Aparecida dos 01 September 2017 (has links)
A obesidade é causada pelo desequilíbrio entre a ingestão alimentar e o gasto energético corporal, com o armazenamento de energia na forma de gordura, no tecido adiposo. A obesidade causa alterações metabólicas, como resistência à insulina e dislipidemia, além de aumento de adipocinas e citocinas pró-inflamatórias. Este trabalho investigou a influência de polimorfismos nos genes da perilipina 1 (PLINl), visfatina (NAMPT) , resistina (RETN) e grelina (GHRL) na adiposidade e no perfil metabólico e inflamatório, antes e após um programa de orientação nutricional. Foram selecionados indivíduos obesos (OB, n=214), sobrepeso (SOB, n=71) e não obesos (NOB, n=69), com idade de 30 a 70 anos. Foram obtidos dados clínicos, antropométricos e de composição corporal. O recordatório de 24h foi aplicado a 87 indivíduos obesos para avaliação de consumo alimentar, antes e após o programa de orientação nutricional. Foi obtido sangue para extração de DNA e para analisar parâmetros laboratoriais (perfil lipídico e glicêmico, marcadores inflamatórios e adipocinas). Polimorfismos dos genes PLINl, NAMPT, RETN e GHRL foram analisados por PCR em tempo real. O grupo OB teve perfil antropométrico alterado e risco aumentado de hipertensão, diabetes tipo 2 e dislipidemia em comparação com os grupos SOB e NOB (p<0,05). As concentrações de glicose, colesterol total, LDL colesterol, VLDL colesterol, triglicérides, apolipoproteína B (ApoB), interleucina 1β (IL-l β) e fator de necrose tumoral alfa (TNFα) foram maiores e as concentrações de HDL colesterol e apolipoproteina AI (apoAI) foram menores, no grupo OB que nos outros grupos (p<0,05). As frequências dos polimorfismos genéticos do grupo total foram similares as de outras populações. Os polimorfismos NAMPT rs1319501 C>T e rs10763861 C>T foram associados com obesidade (p<0,05). Os polimorfismos genéticos não influenciaram o perfil antropométrico do grupo total (p>0,05), mas no grupo de obesos, o polimorfismo GHRL rs4684677 T>A foi relacionado com maior porcentagem de gordura corporal (p=0,043). Após a orientação nutricional, observou-se diminuição da ingestão de calorias e do consumo de carboidratos, gorduras totais, sódio, magnésio e betacaroteno (p<0,05). Os polimorfismos genéticos não influenciaram o perfil antropométrico e o consumo alimentar de obesos, após a orientação nutricional. Em conclusão, polimorfismos dos genes NAMPT e GHRL contribuem para a adiposidade, mas não influenciam o comportamento alimentar e o perfil antropométrico, após orientação nutricional. / Obesity is caused by the imbalance between food intake and body energy expenditure, with the storage of energy in the form of fat, in adipose tissue. Obesity causes metabolic changes, such as insulin resistance and dyslipidemia, and an increase in adipokines and pro-inflammatory cytokines. This work investigated the influence of polymorphisms in the perilipine 1 (PLINI) , visfatin (NAMPT) , resistin (RETN) and ghrelin (GHRL) genes on adiposity and metabolic and inflammatory profile, before and after a nutritional orientation programo Obese (OB, n=214), overweight (SOB, n=71) and nonobese subjects (NOB, n=69), aged 30 to 70 years, were selected. ClinicaI, anthropometric and body composition data were obtained. The 24-hour dietary recall was applied to 87 obese subjects to eva1uate food intake before and after the nutritiona1 orientation programo Blood was obtained for DNA extraction and to analyze 1aboratory parameters (lipid and glycemic profile, inflammatory markers and adipokines). Po1ymorphisms of the PLINI, NAMPT, RETN and GHRL genes were analyzed by real-time PCR. The OB group had altered anthropometric profile and increased risk for hypertension, type 2 diabetes and dyslipidemia in comparison with SOB and NOB groups (p <0.05). Concentrations of glucose, total cholesterol, LDL cholesterol, VLDL cholesterol, triglycerides, apolipoprotein B (ApoB), interleukin 1β (IL-1β) and tumor necrosis factor alpha (TNFα) were higher and the concentrations ofHDL cholesterol and apolipoprotein AI (apoAI) were lower in the OB than in the other groups (p <0.05). The frequencies of the genetic polymorphisms of the total group were similar to those of other populations. NAMPT rs1319501 C> T and rs10763861 C> T polymorphisms were associated with obesity (p <0.05). Genetic polymorphisms did not influence the anthropometric profile ofthe total group (p> 0.05), but in the obese group, the GHRL rs4684677 T> A polymorphism was related to a higher body fat percentage (p = 0.043). After nutritional orientation, a decrease in calorie intake and in the consumption of carbohydrates, total fats, sodium, magnesium and beta-carotene CP <0.05) were observed. Genetic polymorphisms did not influence the anthropometric profile and the dietary intake of obese individuaIs after nutritional orientation. In conclusion, NAMPT and GHRL gene polymorphisms contribute to adiposity but do not influence dietary behavior and anthropometric profile after nutritional orientation.
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Relação de polimorfismos nos genes da perilipina 1, visfatina, resistina e grelina com a resposta a um programa de orientação nutricional para a redução de peso corporal / Relationship of polymorphisms in the perilipine 1, visfatin, resistin and ghrelin genes with the response to the nutritional orientation program for the reduction of body weightMarina Aparecida dos Santos 01 September 2017 (has links)
A obesidade é causada pelo desequilíbrio entre a ingestão alimentar e o gasto energético corporal, com o armazenamento de energia na forma de gordura, no tecido adiposo. A obesidade causa alterações metabólicas, como resistência à insulina e dislipidemia, além de aumento de adipocinas e citocinas pró-inflamatórias. Este trabalho investigou a influência de polimorfismos nos genes da perilipina 1 (PLINl), visfatina (NAMPT) , resistina (RETN) e grelina (GHRL) na adiposidade e no perfil metabólico e inflamatório, antes e após um programa de orientação nutricional. Foram selecionados indivíduos obesos (OB, n=214), sobrepeso (SOB, n=71) e não obesos (NOB, n=69), com idade de 30 a 70 anos. Foram obtidos dados clínicos, antropométricos e de composição corporal. O recordatório de 24h foi aplicado a 87 indivíduos obesos para avaliação de consumo alimentar, antes e após o programa de orientação nutricional. Foi obtido sangue para extração de DNA e para analisar parâmetros laboratoriais (perfil lipídico e glicêmico, marcadores inflamatórios e adipocinas). Polimorfismos dos genes PLINl, NAMPT, RETN e GHRL foram analisados por PCR em tempo real. O grupo OB teve perfil antropométrico alterado e risco aumentado de hipertensão, diabetes tipo 2 e dislipidemia em comparação com os grupos SOB e NOB (p<0,05). As concentrações de glicose, colesterol total, LDL colesterol, VLDL colesterol, triglicérides, apolipoproteína B (ApoB), interleucina 1β (IL-l β) e fator de necrose tumoral alfa (TNFα) foram maiores e as concentrações de HDL colesterol e apolipoproteina AI (apoAI) foram menores, no grupo OB que nos outros grupos (p<0,05). As frequências dos polimorfismos genéticos do grupo total foram similares as de outras populações. Os polimorfismos NAMPT rs1319501 C>T e rs10763861 C>T foram associados com obesidade (p<0,05). Os polimorfismos genéticos não influenciaram o perfil antropométrico do grupo total (p>0,05), mas no grupo de obesos, o polimorfismo GHRL rs4684677 T>A foi relacionado com maior porcentagem de gordura corporal (p=0,043). Após a orientação nutricional, observou-se diminuição da ingestão de calorias e do consumo de carboidratos, gorduras totais, sódio, magnésio e betacaroteno (p<0,05). Os polimorfismos genéticos não influenciaram o perfil antropométrico e o consumo alimentar de obesos, após a orientação nutricional. Em conclusão, polimorfismos dos genes NAMPT e GHRL contribuem para a adiposidade, mas não influenciam o comportamento alimentar e o perfil antropométrico, após orientação nutricional. / Obesity is caused by the imbalance between food intake and body energy expenditure, with the storage of energy in the form of fat, in adipose tissue. Obesity causes metabolic changes, such as insulin resistance and dyslipidemia, and an increase in adipokines and pro-inflammatory cytokines. This work investigated the influence of polymorphisms in the perilipine 1 (PLINI) , visfatin (NAMPT) , resistin (RETN) and ghrelin (GHRL) genes on adiposity and metabolic and inflammatory profile, before and after a nutritional orientation programo Obese (OB, n=214), overweight (SOB, n=71) and nonobese subjects (NOB, n=69), aged 30 to 70 years, were selected. ClinicaI, anthropometric and body composition data were obtained. The 24-hour dietary recall was applied to 87 obese subjects to eva1uate food intake before and after the nutritiona1 orientation programo Blood was obtained for DNA extraction and to analyze 1aboratory parameters (lipid and glycemic profile, inflammatory markers and adipokines). Po1ymorphisms of the PLINI, NAMPT, RETN and GHRL genes were analyzed by real-time PCR. The OB group had altered anthropometric profile and increased risk for hypertension, type 2 diabetes and dyslipidemia in comparison with SOB and NOB groups (p <0.05). Concentrations of glucose, total cholesterol, LDL cholesterol, VLDL cholesterol, triglycerides, apolipoprotein B (ApoB), interleukin 1β (IL-1β) and tumor necrosis factor alpha (TNFα) were higher and the concentrations ofHDL cholesterol and apolipoprotein AI (apoAI) were lower in the OB than in the other groups (p <0.05). The frequencies of the genetic polymorphisms of the total group were similar to those of other populations. NAMPT rs1319501 C> T and rs10763861 C> T polymorphisms were associated with obesity (p <0.05). Genetic polymorphisms did not influence the anthropometric profile ofthe total group (p> 0.05), but in the obese group, the GHRL rs4684677 T> A polymorphism was related to a higher body fat percentage (p = 0.043). After nutritional orientation, a decrease in calorie intake and in the consumption of carbohydrates, total fats, sodium, magnesium and beta-carotene CP <0.05) were observed. Genetic polymorphisms did not influence the anthropometric profile and the dietary intake of obese individuaIs after nutritional orientation. In conclusion, NAMPT and GHRL gene polymorphisms contribute to adiposity but do not influence dietary behavior and anthropometric profile after nutritional orientation.
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