RESUMO
Genome wide association studies revealed an association of the single nucleotide polymorphism rs11708067 within the ADCY5 gene--encoding adenylate cyclase 5--with increased type 2 diabetes (T2D) risk and higher fasting glucose. However, it remains unclear whether the association between ADCY5 variants and glycemic traits may involve adipose tissue (AT) related mechanisms. We therefore tested the hypothesis that ADCY5 mRNA expression in human and mouse AT is related to obesity, fat distribution, T2D in humans and high fat diet (HFD) in mice. We measured ADCY5 mRNA expression in paired samples of visceral and subcutaneous adipose tissue from 244 individuals with a wide range of body weight and parameters of hyperglycemia, which have been genotyped for rs11708067. In addition, AT ADCY5 mRNA was assessed in C57BL/6NTac which underwent a 10 weeks standard chow (n = 6) or high fat diet (HFD, n = 6). In humans, visceral ADCY5 expression is significantly higher in obese compared to lean individuals. ADCY5 expression correlates with BMI, body fat mass, circulating leptin, fat distribution, waist and hip circumference, but not with fasting plasma glucose and HbA1c. Adcy5 expression in mouse AT is significantly higher after a HFD compared to chow (p<0.05). Importantly, rs11708067 is not associated with ADCY5 mRNA expression levels in either fat depot in any of the genetic models tested. Our results suggest that changes in AT ADCY5 expression are related to obesity and fat distribution, but not with impaired glucose metabolism and T2D. However, altered ADCY5 expression in AT does not seem to be the mechanism underlying the association between rs11708067 and increased T2D risk.
Assuntos
Adenilil Ciclases/genética , Tecido Adiposo/enzimologia , Regulação Enzimológica da Expressão Gênica , Obesidade/enzimologia , Obesidade/genética , Adenilil Ciclases/metabolismo , Adiposidade , Animais , Dieta Hiperlipídica , Feminino , Predisposição Genética para Doença , Glucose/metabolismo , Humanos , Inflamação/genética , Inflamação/patologia , Insulina/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único/genética , Característica Quantitativa Herdável , RNA Mensageiro/genética , RNA Mensageiro/metabolismoRESUMO
We have recently demonstrated that C57BL/6NTac and C57BL/6JRj substrains are significantly different in their response to high-fat diet-induced obesity (DIO). The C57BL/6JRj substrain seems to be protected from DIO and genetic differences between C57BL/6J and C57BL/6N substrains at 11 single nucleotide polymorphism (SNP) loci have been identified. To define genetic variants as well as differences in parameters of glucose homeostasis and insulin sensitivity between C57BL/6NTac and C57BL/6JRj substrains that may explain the different response to DIO, we analyzed 208 first backcross (BC1) hybrids of C57BL/6NTac and C57BL/6JRj [(C57BL/6NTac × C57BL/6JRj)F1 × C57BL/6NTac] mice. Body weight, epigonadal and subcutaneous fat mass, circulating leptin, as well as parameters of glucose metabolism were measured after 10 wk of high-fat diet (HFD). Genetic profiling of BC1 hybrids were performed using TaqMan SNP genotyping assays. Furthermore, to assess whether SNP polymorphisms could affect mRNA level, we carried out gene expression analysis in murine liver samples. Human subcutaneous adipose tissue was used to verify murine data of SNAP29. We identified four sex-specific variants that are associated with the extent of HFD-induced weight gain and fat depot mass. BC1 hybrids carrying the combination of risk or beneficial alleles exhibit the phenotypical extremes of the parental strains. Murine and human SC expression analysis revealed Snap29 as strongest candidate. Our data indicate an important role of these loci in responsiveness to HFD-induced obesity and suggest genes of the synaptic vesicle release system such as Snap29 being involved in the regulation of high-fat DIO.
Assuntos
Dieta Hiperlipídica/efeitos adversos , Loci Gênicos/genética , Obesidade/genética , Tecido Adiposo/metabolismo , Alelos , Animais , Peso Corporal/genética , Feminino , Genótipo , Glucose/metabolismo , Humanos , Leptina/sangue , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Obesidade/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Proteínas de Transporte Vesicular/genética , Proteínas de Transporte Vesicular/metabolismo , Aumento de Peso/genéticaRESUMO
The C57BL/6 (B6) is one of the oldest inbred mouse strains. It has been widely used as control strain in metabolism research for many decades. Preliminary data from our lab indicated that C57BL/6JRj mice are not responding to diet induced obesity. Therefore, the aim of this study was to compare the two different B6 substrains, C57BL/6NTac and C57BL/6JRj, in regard to their response to diet induced obesity (DIO) and to investigate genetic differences which may explain such phenotypic differences. Sixteen male mice of C57BL/6NTac and C57BL/6JRj were fed a high fat diet (HFD) or standard chow diet (SD) for 10 weeks. Phenotypic characterization included measurements of bodyweight, physical activity, food intake and relative epigonadal fat mass. Genetic differences between both substrains were analyzed using a panel of 1449 single nucleotide polymorphism (SNP) markers. Our study revealed that C57BL/6JRj mice are protected against DIO independently from food intake and physical activity. Genetic SNP analysis among C57BL/6 mice identified genetic differences in at least 11 SNPs. Our data strongly support the importance of attention on the genetic background in obesity research.