RARRES2, encoding the novel adipokine chemerin, is a genetic determinant of disproportionate regional body fat distribution: a comparative magnetic resonance imaging study
Introduction
Obesity is a growing public health problem worldwide. Generalized obesity is frequently associated with metabolic comorbidities, including glucose intolerance, insulin resistance, pancreatic β-cell dysfunction, and type 2 diabetes mellitus [1]. However, an increasing body of evidence supports the importance of body fat distribution in the development of the aforementioned metabolic disorders [2]. Visceral adipose tissue (VAT) mass was identified as a strong and independent predictor of obesity-related disorders [3]. Thus, individuals who are not obese according to body mass index (BMI) but have large VAT depots are at increased risk for adverse metabolic consequences [4].
Although heritability data for abdominal visceral fat are limited, previous studies clearly indicate, in addition to environmental determinants, the existence of genetic factors in the development of visceral obesity [5], [6]. The genetic determinants of human fat topography that likely differ from those determining fat mass per se [7] may affect modulation of food intake and energy expenditure, lipid metabolism, and adipocyte differentiation [5].
Therefore, the aim of the present study was to test the impact of common genetic variation in the fat mass– and obesity-associated (FTO) gene, the peroxisome proliferator–activated receptor–δ (PPARD) gene, and the retinoic acid receptor responder 2 (RARRES2) gene on regional fat distribution and obesity-related traits, such as insulin resistance and β-cell dysfunction.
The FTO gene was recently identified as a major genetic determinant of adult and childhood obesity by genomewide searches [8], [9], [10] and is suggested to play an important role in the central nervous regulation of calorie balance [11], [12]. The PPARD gene promotes lipid metabolism in peripheral tissues [13]. Recently located to a genetic locus associated with obesity [14], PPARD was shown to affect lifestyle intervention–induced changes in fat mass [15]. The RARRES2 gene encodes the novel adipokine chemerin, also known as tazarotene-induced gene 2, which was recently reported to play a role in adipogenesis and adipocyte metabolism [16].
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Subjects
The 337 nondiabetic subjects (subject characteristics shown in Table 1) at an increased risk for type 2 diabetes mellitus (family history of diabetes, history of gestational diabetes, overweight, or impaired glucose tolerance) were recruited from the ongoing Tübingen Family Study for type 2 diabetes mellitus. Relatedness among subjects was less than 1%. All subjects were metabolically characterized by an oral glucose tolerance test (OGTT); a subgroup of 230 subjects was additionally
Characterization and genotyping of a German population at an increased risk for type 2 diabetes mellitus
We genotyped 337 nondiabetic subjects from the southwest of Germany whose clinical characteristics are presented in Table 1. Most (81.4%) of the subjects had a family history of diabetes, that is, at least 1 second-degree relative with type 2 diabetes mellitus. The following tagging SNPs were analyzed: rs1053049, rs6902123, and rs2267668 in PPARD; rs8050136 in FTO; as well as rs3735171, rs10278590, and rs17173608 in RARRES2. All allele frequencies were in Hardy-Weinberg equilibrium (χ2 test, P
Discussion
We found associations of the RARRES2 SNPs rs17173608 and rs10278590 with VAT mass, whereas no associations between these 2 SNPs and NVAT content were detected. These findings suggest that common genetic variation in the RARRES2 gene locus may specifically contribute to the development of visceral adiposity. In contrast, tagging SNPs in the genes FTO and PPARD, both known to modulate fat mass, were not associated with body fat distribution. Interestingly, we did not observe an association
Acknowledgment
We thank all study participants for their cooperation. We thank the International HapMap Consortium for the public allocation of genotype data. We gratefully acknowledge the excellent technical assistance of Anna Bury, Alke Guirguis, Carina Haas, Heike Luz, Melanie Weisser, and Roman Werner. The study was supported in part by grants from the German Research Foundation (KFO 114/2) and the European Community's frame program FP6 EUGENE 2 (LSHM-CT-2004-512013).
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These authors contributed equally to this article.