Novel variations in the adiponectin gene (ADIPOQ) may affect distribution of oligomeric complexes

Leah C Kottyan,Nancy A Crimmins,Walter Banach,Jessica G Woo,Mehdi Keddache,Lawrence M Dolan,Lisa J Martin

doi:10.1186/2193-1801-1-66

Leah C Kottyan, Nancy A Crimmins + Show 5 more

Open Access

https://doi.org/10.1186/2193-1801-1-66

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Abstract

Adiponectin is an obesity related protein that mediates the risk of type 2 diabetes in obese individuals with its anti-inflammatory and insulin-sensitizing properties. To date, five functional variations have been identified in the adiponectin gene. However, these variations are rare, and fail to fully explain adiponectin variability, suggesting unidentified causal variations exist. Thus, our objective was to identify novel, potentially functional amino acid-changing variations in ADIPOQ exonic regions and relate them to oligomeric forms of adiponectin in serum. We sequenced ADIPOQ exons in 30 adolescents chosen from a school-based cohort based on serum adiponectin and insulin levels. Four coding region changes were identified: a methionine initiation skip (MIS), P32L, R55C, and Y111H, of which R55C and Y111H have been previously identified. Individuals with the novel variations and R55C had low levels of adiponectin and decreased adiponectin oligomerization compared to adolescents with similar body mass index and insulin levels. Further, bioinformatic analysis predicted putative functionality of these variations. In our study, Y111H was unrelated to total circulating adiponectin or adiponectin oligomerization. Given the disruption of adiponectin oligomerization in the individuals with MIS, P32L, and R55C coding changes, these variations may lead to increased metabolic disease risk and warrant further examination in larger cohorts.

Highlights

Obesity is a major problem in the United States with over two thirds of adults and one third of adolescents classified as overweight or obese Ogden et al (2012)
In lean individuals Martin et al (2005) and mice Maeda et al (2002), adiponectin concentrations are not associated with insulin sensitivity; yet, in the context of obesity adiponectin concentrations show strong association with insulin levels (Maeda et al 2002; Martin et al 2005)
G > A abbreviated as methionine initiation skip (MIS)), P32L, R55C, and Y111H (Figure 1)

Summary

Introduction

Obesity is a major problem in the United States with over two thirds of adults and one third of adolescents classified as overweight or obese Ogden et al (2012). While excess weight is a risk factor for type 2 diabetes, most obese individuals do not develop type 2 diabetes (T2D) (Boyle et al 2010; Eckel et al 2011; Writing Group for the Search for Diabetes in Youth Study Group et al 2007). Adiponectin may help explain the increased T2D risk in some obese individuals. Adiponectin has anti-inflammatory and insulin-sensitizing properties, and low adiponectin levels precede development of insulin resistance and T2D (Hotta et al 2001; Lindsay et al 2002). Adiponectin’s effects on insulin sensitivity are more clinically relevant in obese individuals. In lean individuals Martin et al (2005) and mice Maeda et al (2002), adiponectin concentrations are not associated with insulin sensitivity; yet, in the context of obesity adiponectin concentrations show strong association with insulin levels (Maeda et al 2002; Martin et al 2005)

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