| Summary: | <p>Abstract</p> <p>Background</p> <p>The estrogen receptors α and β (<it>ESR1, ESR2</it>) have been implicated in adiposity, lipid metabolism and feeding behaviour. In this report we analyse <it>ESR1 </it>and <it>ESR2 </it>gene single nucleotide polymorphisms (SNPs) for association with obesity. We also relate adipose tissue <it>ESR1 </it>mRNA levels and <it>ESR1 </it>SNPs to adipocyte lipolysis and lipogenesis phenotypes.</p> <p>Methods</p> <p>23 <it>ESR1 </it>and 11 <it>ESR2 </it>tag-SNPs, covering most of the common haplotype variation in each gene according to HAPMAP data, were analysed by Chi<sup>2 </sup>for association with obesity in a cohort comprising 705 adults with severe obesity and 402 lean individuals. Results were replicated in a cohort comprising 837 obese and 613 lean subjects. About 80% of both cohorts comprised women and 20% men. Adipose tissue <it>ESR1 </it>mRNA was quantified in 122 women and related to lipolysis and lipogenesis by multiple regression. <it>ESR1 </it>SNPs were analysed for association with adipocyte lipolysis and lipogenesis phenotypes in 204 obese women by simple regression.</p> <p>Results</p> <p>No <it>ESR1 </it>SNP was associated with obesity. Five <it>ESR2 </it>SNPs displayed nominal significant allelic association with obesity in women and one in men. The two <it>ESR2 </it>SNPs associated with obesity with nominal P value < 0.01 were genotyped in a second cohort where no association with obesity was observed. There was an inverse correlation between <it>ESR1 </it>mRNA levels in abdominal subcutaneous (sc) adipose tissue and basal lipolysis, as well as responsiveness to adrenoceptor agonists independent of age and BMI (P value 0.009–0.045). <it>ESR1 </it>rs532010 was associated with lipolytic sensitivity to noradrenaline (nominal P value 0.012), and <it>ESR1 </it>rs1884051 with responsiveness to the non-selective beta-adrenoceptor agonist isoprenaline (nominal P value 0.05). These associations became non-significant after Bonferroni correction.</p> <p>Conclusion</p> <p><it>ESR1 </it>gene alleles are unlikely to be a major cause of obesity in women. A minor importance of <it>ESR2 </it>on severe obesity cannot be excluded. The inverse correlation between <it>ESR1 </it>mRNA levels and lipolytic responsiveness to adrenoceptor agonists implies that low adipose tissue <it>ESR1 </it>levels attenuate catecholamine resistance in sc fat cells of obese women hereby contributing to loss of sc and gain of visceral fat. There is no evidence for a genetic impact of <it>ESR1 </it>on lipolysis or lipogenesis.</p>
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