Similar to adiponectin, serum levels of osteoprotegerin are associated with obesity in healthy subjects☆,☆☆
Introduction
There has been a dramatic increase in the prevalence of obesity during the past 2 decades. Increased adiposity is associated with the development of insulin resistance and is a risk factor for type 2 diabetes mellitus [1] and vascular dysfunction [2], [3]. Increasingly, it is recognized that adipose tissue is an active metabolic organ releasing adipokines into the circulation that influence insulin action and contribute to vascular dysfunction. Adiponectin and tumor necrosis factor (TNF)–α are 2 such adipokines. A reduction in adiponectin and an increase in TNF-α production have been shown to reduce insulin sensitivity [4], [5], [6] and increase vascular dysfunction [7].
The vascular endothelium can also produce and release glycoproteins into the circulation; yet little is know about their effect, if any, on insulin action. Osteoprotegerin (OPG) is a member of the TNF receptor superfamily [8] that is released into the circulation as a soluble glycoprotein [9] and binds to receptor activator of nuclear factor–κβ ligand (RANKL) and TNF-related apoptosis-inducing ligand (TRAIL) [10], [11]. Osteoprotegerin is present in a number of tissues including bone where it inhibits osteoclastogenesis, the immune system, and the vasculature. Osteoprotegerin and RANKL are highly expressed in vascular smooth muscle [12] and endothelial cells [13], [14], with protein content 500 to 1000 times greater than circulating levels [15], [16]. In animal studies, OPG-deficient mice exhibit severe aortic and renal calcification [17]; yet the significance of OPG and RANKL within the vasculature is not fully understood.
In humans, serum OPG correlates with the degree of underlying coronary artery calcification in patients with type 2 diabetes mellitus [18] and the severity of coronary artery disease [19], [20], [21], suggesting an important link between OPG and vascular dysfunction. TRAIL is expressed and secreted by cells of the immune system and appears to exert an effect on the vasculature. It may contribute to plague instability but others have shown the administration of TRAIL to atherogenic apolipoprotein E-/- mice induced plaque regression [22]. Despite the fact that weight gain is a risk factor for type 2 diabetes mellitus and cardiovascular disease, it is not known if obesity contributes to the changes in OPG and TRAIL observed in these studies. Therefore, the purpose of this study was to determine if differences in body mass index (BMI) and insulin sensitivity influence the concentrations of serum OPG and TRAIL in subjects who do not have cardiovascular or metabolic disease.
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Subjects
Participants were recruited by means of an open call for volunteers who were free from cardiovascular and metabolic disease and not taking any medication. In total, 136 subjects volunteered to participate in the study. Of these, 36 were excluded because of undiagnosed hypertension, impaired glucose tolerance, hyperlipidemia, and an abnormal 12-lead electrocardiogram (ECG) result at rest or in response to exercise. The final cohort that met the inclusion criteria consisted of 100 subjects, aged
Physical characteristics
The physical and metabolic characteristics for the normal-weight, overweight, and obese subjects are presented in Table 1. Age and sex distribution was similar for the 3 groups; but there were significant differences in BMI, percentage body fat, waist circumference, and waist-to-hip ratio. In addition, the obese group had significantly higher systolic and diastolic blood pressure and lower aerobic capacity as assessed by VO2max (mL·kg·min−1) compared with the other 2 groups.
Metabolic phenotype
All subjects had
Discussion
The main finding from our study is that obese subjects, with normal glucose tolerance and free from cardiovascular disease, have lower circulating OPG when compared with normal-weight and overweight individuals. The purpose of this study was to examine the relationship between insulin sensitivity, obesity, and OPG in a well characterized, healthy population free from cardiovascular and metabolic disease. The positive relationship between OPG and adiponectin and the negative association with
Acknowledgment
The authors would like to thank all those participants who took part in the study and to acknowledge the assistance of student volunteers who assisted with the data collection. This study was funded by an EMBARK award to DTA from the Irish Research Council for Science, Engineering, and Technology.
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Institutional approval: This study was approved by the Dublin City University Research Ethics Committee.
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Author contributions: design and conduct of the study (DTA, EPO'S, DS, DJO'G); data collection and analysis (DTA, EPO'S, CD, ND,RKC, NMcC, NMM); data interpretation (DTA, EPO'S, CD, ND, RKC, NMcC, NMM, DS, DJO'G); manuscript writing (DTA, EPO'S, CD, DS, DJO'G).