Abstract
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.
Highlights
In a meta-analysis of genome wide association studies (GWAS) several genetic loci associated with fasting diabetes-related quantitative traits (fasting plasma glucose, fasting plasma insulin, beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) have been identified [1]
We investigated ADCY5 mRNA expression in visceral and subcutaneous adipose tissue in 244 individuals (157 women and 87 men), which have been further classified into patients with
Our data do not support the hypothesis that ADCY5 polymorphisms contribute to altered ADCY5 gene expression in adipose tissue (AT)
Summary
In a meta-analysis of genome wide association studies (GWAS) several genetic loci associated with fasting diabetes-related quantitative traits (fasting plasma glucose, fasting plasma insulin, beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) have been identified [1]. Single nucleotide polymorphisms (SNPs) within the ADCY5 gene, which encodes adenylate cyclase 5, are associated with elevated fasting glucose and increased risk to develop type 2 diabetes (T2D) [1]. Associations between the major allele (C) of ADCY5 variant rs2877716 and decreased fasting plasma insulin, peak insulin and increased QUICKI and Matsuda insulin sensitivity index were found in obese children [5]. ADCY5 is a member of the adenylate cyclase family, which consists of twelve domain transmembrane proteins that catalyzes the conversion of ATP to cyclic AMP, the second messenger for G protein coupled receptors [6]. Adenylate cyclases (AC) are ATP-pyrophoshate lyases which convert Adenosine triphosphate (ATP) into the second messenger cyclic adenosine monophosphate (cAMP) and pyrophosphate [6]. ADCY5 has been described to mediate renin release [7], influence heart rate [8] and plays a role in dopamine homeostasis in the central nervous system [9]
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